Carnosine as a Neuroprotective Agent? (2023)

Carnosine as a neuroprotective agent

Wise Young, Ph.D.,M.D.

W. M. Keck Center forCollaborative Neuroscience

Rutgers University,Piscataway, New Jersey 08854

Email: wisey@pipeline.com

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Injury disrupts cells and causes an inrush of calciumions. The calcium ions disrupts mitochondria,causing release of oxygen free radicals.In addition, calcium ions activate many intracellular enzymes thatdigest the cell, including phospholipases, phosphatases, nucleases, andproteinases. Phospholipases break down membranes, releasing free fattyacids. One fatty acid, calledarachidonic acid, is broken down by an enzyme called cycloxygenase (COX) toproduce prostaglandins and leukotrienes.Prostaglandins cause inflammation.These biochemical reactions to injury contribute to progressive tissuedamage after injury [1].

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Many chemicals are antioxidants, including vitamin C and E,glutathione, naloxone (NX), methylprednisolone (MP), and tirilazad mesylate(TM). In 1990, the Second NationalAcute Spinal Cord Injury Study (NASCIS 2) [2, 3] compared high-dose MP and NX,finding that MP (30 mg/kg + 5.4 mg/kg/hr x 23 hr) improves motor and sensoryrecovery significantly more than placebo controls or NX (5.4 mg/kg + 3 mg/kg/hrx 23 hr). In addition to being anantioxidant, MP is anti-inflammatory. TM is a potent antioxidant. The NASCIS 3 trial [4, 5] compared methylprednisoloneand tirilazad and found that the two drugs had equivalent effects on recovery whenstarted within 3 hours but a 48-hour course of MP was more effective than a48-hour course of tirilazad or a 24-hour course of MP. Therefore, the recommended therapy for acutespinal cord injury is a 24-hour course of MP if treatment can be started within3 hours and a 48-hour course of MP if started between 3-8 hours [6, 7].

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Carnosine is a natural antioxidant dipeptide composed on theamino acids histidine and alanine. Carnosine should not be confused carnitine which is an aminoacid that is responsible for transport of fatty acids in mitochondria. Carnosine is found in brain, heart,skin, muscles, kidneys, gut, and other tissues. It is widely used as a dietary supplement (500 mg per day) andhas been suggested to be potentially useful for treating AlzheimerÕs disease [8, 9], autism [10], cataract prevention [11], brain ischemia [12], ParkinsonÕs disease [13], DownÕs syndrome [14], epilepsy [15, 16], schistosomiasis [17], and aging [18-21]. Oral supplements of carnosine significantly increase carnosinelevels in skeletal muscles [22]. Intracerebroventricular injections of carnosine suppresses renalsympathetic nerve activity and blood pressure [23]. It also seems to reduce food intake in a dose-dependentfashion when injected intracerebroventricularly [24]

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Early studies suggested that carnosine is anantioxidant. In 1984, Dupin, etal. [25] reported that carnosineprotected frog muscle subjected to ascorbic acid-dependent lipid peroxidation. Krichevskaia, et al. [26] used homocarnosine (100mg/kg) to treat animals subjected to hyperbaric oxygen and found that itprevented lipid peroxidation in brains.Boldyrev [27-32] suggested that carnosineprotected membranes and prevented losses of membrane [33]. Kohen, et al. [34] showed that carnosine, homocarnosine,anserine, and other histidine containing peptides trapped peroxyl radicalswhile Aruoma, et al. [35] found that these peptidestrapped hydroxyl radicals. Babizhayev[36, 37] reported that carnosinechelates metals, hydroxyl and lipid peroxyl radicals.

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The antioxidant mechanisms of carnosine, however, have beencontroversial. Gorbunov & Erin [38] found that carnosine does notinteract directly with active free radicals. Kohen, et al. [39] subsequently reported that copper-carnosinemay acts like superoxide dymutase, an enzyme that breaks down superoxide. Salim-Hanna, et al. [40] found that carnosine protectsenzyme activity in tissues. MacFarlane,et al. [41] found that carnosine arepotent pH buffers. Severalinvestigators [42-44] have reported thatzinc-carnosine and other metal-carnosine chelates inhibits lipid peroxidation [45]. Decker, et al., [46] suggested that the mainantioxidant mechanism of carnosine is due to copper chelation. Trombley, et al. [47, 48] suggest that carnosinemodulates neuronal activity and synapses.Severina & Busygonia [49-52] reported that carnosineinhibits guanylate cylase. Snimoniia, et al. [53] and others [54] found that carnosine protectsNa/K ATPase. Prokopieva, et al. [55] showed that carnosineprevents hemolysis of red blood cells but through mechanisms other thanantioxidation or pH buffering. In1993, Boldyrev [56-59] concluded that the knownbiological effects of carnosine cannot be explained only by its antioxidantproperties.

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Many laboratories reported that carnosine has a variety of beneficialeffects on cells and tissues [19, 60-65], including pheochromocytoma [66, 67], heart [68-76], intestines [77], liver [78], skeletal muscles [79, 80]. It appears to prevent cataract formation [81]. Reeve, et al. [82] found that carnosinepotentiated immune reactions. Carnosinealso retards senescence of cultured human fibroblasts [83]. Shohami, et al. [84] showed that closed headinjury induces whole body oxidative stress that reduced a variety of putative tissueantioxidants, including carnosine.

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Carnosine is present in the central nervous system. Early studies showed that mouseolfactory bulb bound L-carnosine [85]. Hipkiss [64] proposed that carnosine is anaturally occurring suppressor of oxidative damage in olfactory neurons. DeMarchis, et al. [86] found carnosine in matureolfactory receptor neurons, a subset of glial cells, and neural progenitor cellsin rat brain. Carnitine is also present in olfactory neurons [47] and visual system [87]. Hoffman, et al. [88] found that ratoligodendroglial cells made carnosine and astrocytes took up carnitine. Baslow, et al. [89] showed that carnosine is synthesizedin macroglia and ependymal cells [90] that may not be able tohydrolyze them and therefore releases them [91]. Sunderman, et al. [92] proposed that carnosine mayprotect olfactory neurons by complexing metals (e.g. Al, Bi, Cu, Mn, Zn). Interestingly, anti-epileptic drugs topiramate[15, 93], gabapentin [94], vigabatrin [95, 96] increase homocarnosine levelsin human brain. Homocarnosine levelsare related to GABA [97].

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Despite the abundance of data suggesting that carnosine andrelated compounds have antioxidant properties and cellular protective effects, severalinvestigators have suggestd that carnosine is an endogenous neuroprotector [12], relatively little data isavailable concerning its use as a neuroprotective agent. Pubill, et al. [98] reported that carnosineprevents methamphetamine-induced gliosis.Gallant, et al. [99] gave rats dietary carosineand found that it reduced mortality and improved behavioral recovery of ratssubjected to common carotid artery occlusion. Carnosine, surprisingly, has notbeen tested in any model of spinal cord injury, whether chronic or acute.

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References Cited

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1. Hall ED andSpringer JE (2004). Neuroprotection and Acute Spinal Cord Injury: AReappraisal. Neurorx. 1: 80-100. Spinal Cord and Brain Injury Research Center,University of Kentucky Chandler Medical Center, Lexington, Kentucky 40536. Ithas long been recognized that much of the post-traumatic degeneration of thespinal cord following injury is caused by a multi-factorial secondary injuryprocess that occurs during the first minutes, hours, and days after spinal cordinjury (SCI). A key biochemical event in that process is reactiveoxygen-induced lipid peroxidation (LP). In 1990 the results of the SecondNational Acute Spinal Cord Injury Study (NASCIS II) were published, whichshowed that the administration of a high-dose regimen of the glucocorticoid steroidmethylprednisolone (MP), which had been previously shown to inhibitpost-traumatic LP in animal models of SCI, could improve neurological recoveryin spinal-cord-injured humans. This resulted in the registration of high-doseMP for acute SCI in several countries, although not in the U.S. Nevertheless,this treatment quickly became the standard of care for acute SCI since the drugwas already on the U.S. market for many other indications. Subsequently, it wasdemonstrated that the non-glucocorticoid 21-aminosteroid tirilazad couldduplicate the antioxidant neuroprotective efficacy of MP in SCI models, andevidence of human efficacy was obtained in a third NASCIS trial (NASCIS III).In recent years, the use of high-dose MP in acute SCI has become controversiallargely on the basis of the risk of serious adverse effects versus what isperceived to be on average a modest neurological benefit. The opiate receptorantagonist naloxone was also tested in NASCIS II based upon the demonstrationof its beneficial effects in SCI models. Although it did not a significantoverall effect, some evidence of efficacy was seen in incomplete (i.e.,paretic) patients. The monosialoganglioside GM1 has also been examined in arecently completed clinical trial in which the patients first receivedhigh-dose MP treatment. However, GM1 failed to show any evidence of asignificant enhancement in the extent of neurological recovery over the levelafforded by MP therapy alone. The present paper reviews the past development ofMP, naloxone, tirilazad, and GM1 for acute SCI, the ongoing MP-SCI controversy,identifies the regulatory complications involved in future SCI drugdevelopment, and suggests some promising neuroprotective approaches that couldeither replace or be used in combination with high-dose MP.

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2. Bracken MB(1991). Treatment of acute spinal cord injury with methylprednisolone: resultsof a multicenter, randomized clinical trial. J Neurotrauma. 8 Suppl 1: S47-50;discussion S51-2. Department of Epidemiology and Public Health, Yale UniversitySchool of Medicine, New Haven, Connecticut. Although some evidence ofneurological improvement with naloxone exists in this trial, the improvementwas never significantly better than that seen for placebo. Methylprednisolone(MP) was effective in reducing some of the permanent paralysis after acutespinal cord injury at the doses studied, but only when treatment began within 8h after injury. There is currently no support for the administration of higheror lower doses of the drug and an apparent contraindication to initiatingadministration of MP at any dose more than 8 h after injury.

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3. Bracken MB,Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, Eisenberg HM, Flamm E,Leo-Summers L, Maroon J and et al. (1990). A randomized, controlled trial ofmethylprednisolone or naloxone in the treatment of acute spinal-cord injury.Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med.322: 1405-11. Department of Epidemiology and Public Health, Yale UniversitySchool of Medicine, New Haven, CT 06510. Studies in animals indicate thatmethylprednisolone and naloxone are both potentially beneficial in acutespinal-cord injury, but whether any treatment is clinically effective remainsuncertain. We evaluated the efficacy and safety of methylprednisolone andnaloxone in a multicenter randomized, double-blind, placebo-controlled trial inpatients with acute spinal-cord injury, 95 percent of whom were treated within14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogramper hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mgper kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23hours. Placebos were given to 171 patients by bolus and infusion. Motor andsensory functions were assessed by systematic neurological examination onadmission and six weeks and six months after injury. After six months thepatients who were treated with methylprednisolone within eight hours of theirinjury had significant improvement as compared with those given placebo inmotor function (neurologic change scores of 16.0 and 11.2, respectively; P =0.03) and sensation to pinprick (change scores of 11.4 and 6.6; P = 0.02) andtouch (change scores, 8.9 and 4.3; P = 0.03). Benefit from methylprednisolonewas seen in patients whose injuries were initially evaluated as neurologicallycomplete, as well as in those believed to have incomplete lesions. The patientstreated with naloxone, or with methylprednisolone more than eight hours aftertheir injury, did not differ in their neurologic outcomes from those givenplacebo. Mortality and major morbidity were similar in all three groups. Weconclude that in patients with acute spinal-cord injury, treatment withmethylprednisolone in the dose used in this study improves neurologic recoverywhen the medication is given in the first eight hours. We also conclude thattreatment with naloxone in the dose used in this study does not improveneurologic recovery after acute spinal-cord injury.

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4. Bracken MB,Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL,Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL, Jr., Piepmeier J,Sonntag VK, Wagner F, Wilberger JE, Winn HR and Young W (1997). Administrationof methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours inthe treatment of acute spinal cord injury. Results of the Third National AcuteSpinal Cord Injury Randomized Controlled Trial. National Acute Spinal CordInjury Study. JAMA. 277: 1597-604. OBJECTIVE: To compare the efficacy ofmethylprednisolone administered for 24 hours with methyprednisoloneadministered for 48 hours or tirilazad mesylate administered for 48 hours inpatients with acute spinal cord injury. DESIGN: Double-blind, randomizedclinical trial. SETTING: Sixteen acute spinal cord injury centers in NorthAmerica. PATIENTS: A total of 499 patients with acute spinal cord injurydiagnosed in National Acute Spinal Cord Injury Study (NASCIS) centers within 8hours of injury. INTERVENTION: All patients received an intravenous bolus ofmethylprednisolone (30 mg/kg) before randomization. Patients in the 24-hourregimen group (n=166) received a methylprednisolone infusion of 5.4 mg/kg perhour for 24 hours, those in the 48-hour regimen group (n=167) received amethylprednisolone infusion of 5.4 mg/kg per hour for 48 hours, and those inthe tirilazad group (n=166) received a 2.5 mg/kg bolus infusion of tirilazadmesylate every 6 hours for 48 hours. MAIN OUTCOME MEASURES: Motor functionchange between initial presentation and at 6 weeks and 6 months after injury,and change in Functional Independence Measure (FIM) assessed at 6 weeks and 6months. RESULTS: Compared with patients treated with methylprednisolone for 24hours, those treated with methylprednisolone for 48 hours showed improved motorrecovery at 6 weeks (P=.09) and 6 months (P=.07) after injury. The effect ofthe 48-hour methylprednisolone regimen was significant at 6 weeks (P=.04) and 6months (P=.01) among patients whose therapy was initiated 3 to 8 hours afterinjury. Patients who received the 48-hour regimen and who started treatment at3 to 8 hours were more likely to improve 1 full neurologic grade (P=.03) at 6 months,to show more improvement in 6-month FIM (P=.08), and to have more severe sepsisand severe pneumonia than patients in the 24-hour methylprednisolone group andthe tirilazad group, but other complications and mortality (P=.97) weresimilar. Patients treated with tirilazad for 48 hours showed motor recoveryrates equivalent to patients who received methylprednisolone for 24 hours.CONCLUSIONS: Patients with acute spinal cord injury who receivemethylprednisolone within 3 hours of injury should be maintained on thetreatment regimen for 24 hours. When methylprednisolone is initiated 3 to 8hours after injury, patients should be maintained on steroid therapy for 48hours.

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5. Bracken MB,Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings MG, HerrDL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL, Jr., Piepmeier J,Sonntag VK, Wagner F, Wilberger JE, Winn HR and Young W (1998).Methylprednisolone or tirilazad mesylate administration after acute spinal cordinjury: 1-year follow up. Results of the third National Acute Spinal CordInjury randomized controlled trial. J Neurosurg. 89: 699-706. Department ofEpidemiology and Public Health, Yale University School of Medicine, New Haven,Connecticut 06520-8034, USA. OBJECT: A randomized double-blind clinical trialwas conducted to compare neurological and functional recovery and morbidity andmortality rates 1 year after acute spinal cord injury in patients who hadreceived a standard 24-hour methylprednisolone regimen (24MP) with those inwhom an identical MP regimen had been delivered for 48 hours (48MP) or thosewho had received a 48-hour tirilazad mesylate (48TM) regimen. METHODS: Patientsfor whom treatment was initiated within 3 hours of injury showed equalneurological and functional recovery in all three treatment groups. Patientsfor whom treatment was delayed more than 3 hours experienced diminished motorfunction recovery in the 24MP group, but those in the 48MP group showed greater1-year motor recovery (recovery scores of 13.7 and 19, respectively, p=0.053).A greater percentage of patients improving three or more neurological gradeswas also observed in the 48MP group (p=0.073). In general, patients treatedwith 48TM recovered equally when compared with those who received 24MP treatments.A corresponding recovery in self care and sphincter control was seen but wasnot statistically significant. Mortality and morbidity rates at 1 year weresimilar in all groups. CONCLUSIONS: For patients in whom MP therapy isinitiated within 3 hours of injury, 24-hour maintenance is appropriate.Patients starting therapy 3 to 8 hours after injury should be maintained on theregimen for 48 hours unless there are complicating medical factors.

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6. Bracken MB(2001). Methylprednisolone and acute spinal cord injury: an update of therandomized evidence. Spine. 26: S47-54. Department of Epidemiology, YaleUniversity School of Medicine, 60 College Street, New Haven, Connecticut 06520,USA. michael.bracken@yale.edu. OBJECTIVES: Randomized trials are widelyrecognized as providing the most reliable evidence for assessing efficacy andsafety of therapeutic interventions. This evidence base is used to evaluate thecurrent status of methylprednisolone (MPSS) in the early treatment of acutespinal cord injury. METHODS: Medline, CINAHL, and other specified databaseswere searched for MeSH headings "methylprednisolone and acute spinal cordinjury." The Cochrane Library and an existing systematic review on the topicwere also searched. RESULTS: Five randomized controlled trials were identifiedthat evaluated high-dose MPSS for acute spinal cord injury. Three trials by theNASCIS group were of high methodologic quality, and a Japanese and French trialof moderate to low, methodologic quality. Meta-analysis of the final result ofthree trials comparing 24-hour high-dose MPSS with placebo or no therapyindicates an average unilateral 4.1 motor function score improvement (95%confidence interval 0.6-7.6, P = 0.02) in patients treated with MPSS. Thisneurologic recovery is likely to be correlated with improved functionalrecovery in some patients. The safety of this regimen of MPSS is evident fromthe spinal cord injury trials and a systematic review of 51 surgical trials ofhigh-dose MPSS. CONCLUSION: High-dose MPSS given within 8 hours of acute spinalcord injury is a safe and modestly effective therapy that may result inimportant clinical recovery for some patients. Further trials are needed toidentify superior pharmacologic therapies and to test drugs that maysequentially influence the postinjury cascade.

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7. Lammertse DP(2004). Update on pharmaceutical trials in acute spinal cord injury. J SpinalCord Med. 27: 319-25. Craig Hospital, Englewood, Colorado 80113-2811, USA. dlammertse@craighospital.org.OBJECTIVE: To review the major pharmacological trials in acute spinal cordinjury (SCI) that have been conducted over the past 25 years. METHODS: Reviewarticle. RESULTS: The publication of the first National Acute Spinal Cord Injury(NASCIS) trial in 1984 ushered in the era of pharmacological trials oftherapies intended to improve neurologic outcome in acute SCI. Subsequenttrials of methylprednisolone sodium succinate (MPSS) and GM-1 have added to theevidence basis that informs the current management practices for acute SCI.CONCLUSION: The last 50 years have seen a conceptual shift from the pessimismof the past to a cautious optimism that the meager prognosis for neurologicrecovery in acute SCI will yield to the progress of medical science. Majoradvances in the understanding of primary and secondary injury mechanisms haveled to the preclinical study of many promising pharmacological therapies, allwith the goal of improving neurologic outcome. A few of these drugs have stoodthe test of animal model experiments and have made it to the forum of humanclinical trials. The NASCIS trials of methylprednisolone have been acknowledgedwidely as the first human studies to claim improved neurologic outcome.Although the results of these trials remain controversial, the MPSS therapythat they reported has been adopted widely by clinicians around the world asthe best currently available, even if not a consensus "standard ofcare." Clearly, the challenge for medical science remains. The search foreffective treatment has only begun.

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8. Hobart LJ, SeibelI, Yeargans GS and Seidler NW (2004). Anti-crosslinking properties ofcarnosine: significance of histidine. Life Sci. 75: 1379-89. Department ofBiochemistry, University of Health Sciences, 1750 Independence Avenue, KansasCity, MO 64106-1453, USA. Carnosine, a histidine-containing dipeptide, is apotential treatment for Alzheimer's disease. There is evidence that carnosineprevents oxidation and glycation, both of which contribute to the crosslinkingof proteins; and protein crosslinking promotes beta-amyloid plaque formation.It was previously shown that carnosine has anti-crosslinking activity, but itis not known which of the chemical constituents are responsible. We tested theindividual amino acids in carnosine (beta-alanine, histidine) as well asmodified forms of histidine (alpha-acetyl-histidine, 1-methyl-histidine) andmethylated carnosine (anserine) using glycation-induced crosslinking ofcytosolic aspartate aminotransferase as our model. beta-Alanine showedanti-crosslinking activity but less than that of carnosine, suggesting that thebeta-amino group is required in preventing protein crosslinking. Interestingly,histidine, which has both alpha-amino and imidazolium groups, was moreeffective than carnosine. Acetylation of histidine's alpha-amino group ormethylation of its imidazolium group abolished anti-crosslinking activity.Furthermore, methylation of carnosine's imidazolium group decreased itsanti-crosslinking activity. The results suggest that histidine is therepresentative structure for an anti-crosslinking agent, containing thenecessary functional groups for optimal protection against crosslinking agents.We propose that the imidazolium group of histidine or carnosine may stabilizeadducts formed at the primary amino group.

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9. Dukic-StefanovicS, Schinzel R, Riederer P and Munch G (2001). AGES in brain ageing:AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology. 2:19-34. Physiological Chemistry I, Biocenter, University of Wurzburg, Germany.In Alzheimer's disease, age-related cellular changes such as compromised energyproduction and increased radical formation are worsened by the presence of AGEsas additional, AD specific stress factors. Intracellular AGEs (most likelyderived from methylglyoxal) crosslink cytoskeletal proteins and render theminsoluble. These aggregates inhibit cellular functions including transportprocesses and contribute to neuronal dysfunction and death. Extracellular AGEs,which accumulate in ageing tissue (but most prominently on long-lived proteindeposits like the senile plaques) exert chronic oxidative stress on neurons. Inaddition, they activate glial cells to produce free radicals (superoxide andNO) and neurotoxic cytokines such as TNF-alpha. Drugs, which inhibit theformation of AGEs by specific chemical mechanisms (AGE-inhibitors), includingaminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate thedevelopment of (AGE-mediated) diabetic complications. Assuming that 'carbonylstress' contributes significantly to the progression of Alzheimer's disease,AGE-inhibitors might also become interesting novel therapeutic drugs fortreatment of AD.

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10. Chez MG, Buchanan CP,Aimonovitch MC, Becker M, Schaefer K, Black C and Komen J (2002). Double-blind,placebo-controlled study of L-carnosine supplementation in children withautistic spectrum disorders. J Child Neurol. 17: 833-7. Research Division,Autism and Epilepsy Specialty Services of Illinois, Ltd, Lake Bluff, IL 60044,USA. mchezmd@interaccess.com. L-Carnosine, a dipeptide, can enhance frontallobe function or be neuroprotective. It can also correlate withgamma-aminobutyric acid (GABA)-homocarnosine interaction, with possibleanticonvulsive effects. We investigated 31 children with autistic spectrumdisorders in an 8-week, double-blinded study to determine if 800 mg L-carnosinedaily would result in observable changes versus placebo. Outcome measures werethe Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, theExpressive and Receptive One-Word Picture Vocabulary tests, and Clinical GlobalImpressions of Change. Children on placebo did not show statisticallysignificant changes. After 8 weeks on L-carnosine, children showed statisticallysignificant improvements on the Gilliam Autism Rating Scale (total score andthe Behavior, Socialization, and Communication subscales) and the ReceptiveOne-Word Picture Vocabulary test (all P < .05). Improved trends were notedon other outcome measures. Although the mechanism of action of L-carnosine isnot well understood, it may enhance neurologic function, perhaps in theenterorhinal or temporal cortex.

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11. Babizhayev MA, Deyev AI,Yermakova VN, Brikman IV and Bours J (2004). Lipid peroxidation and cataracts:N-acetylcarnosine as a therapeutic tool to manage age-related cataracts inhuman and in canine eyes. Drugs R D. 5: 125-39. Innovative Vision ProductsInc., County of New Castle, Delaware, USA. marlbabizhayev2004@yahoo.com.Cataract formation represents a serious problem in the elderly, withapproximately 25% of the population aged >65 years and about 50% aged >80years experiencing a serious loss of vision as a result of this condition. Notonly do cataracts diminish quality of life, they also impose a severe strain onglobal healthcare budgets. In the US, 43% of all visits to ophthalmologists byMedicare patients are associated with cataract. Surgery represents the standardtreatment of this condition, and 1.35 million cataract operations are performedannually in the US, costing 3.5 billion US dollars (year of costing, 1998).Unfortunately, the costs of surgical treatment and the fact that the number ofpatients exceeds surgical capacities result in many patients being blinded bycataracts worldwide. This situation is particularly serious in developingcountries; worldwide 17 million people are blind because of cataract formation,and the problem will grow in parallel with aging of the population. In anyevent, surgical removal of cataracts may not represent the optimal solution.Although generally recognised as being one of the safest operations, there is asignificant complication rate associated with this surgical procedure.Opacification of the posterior lens capsule occurs in 30-50% of patients within2 years of cataract removal and requires laser treatment, a further 0.8%experience retinal detachments, approximately 1% are rehospitalised for cornealproblems, and about 0.1% develop endophthalmitis. Although the risks are small,the large number of procedures performed means that 26,000 individuals developserious complications as a result of cataract surgery annually in the US alone.Thus, risk and cost factors drive the investigation of pharmaceuticalapproaches to the maintenance of lens transparency. The role of freeradical-induced lipid oxidation in the development of cataracts has beenidentified. Initial stages of cataract are characterised by the accumulation ofprimary (diene conjugates, cetodienes) lipid peroxidation (LPO) products, whilein later stages there is a prevalence of LPO fluorescent end-products. Areliable increase in oxiproducts of fatty acyl content of lenticular lipids wasshown by a direct gas chromatography technique producing fatty acidfluorine-substituted derivatives. The lens opacity degree correlates with thelevel of the LPO fluorescent end-product accumulation in its tissue,accompanied by sulfhydryl group oxidation of lens proteins due to a decrease ofreduced glutathione concentration in the lens. The injection of LPO productsinto the vitreous has been shown to induce cataract. It is concluded thatperoxide damage of the lens fibre membranes may be the initial cause ofcataract development. N-acetylcarnosine (as the ophthalmic drug Can-C), hasbeen found to be suitable for the nonsurgical prevention and treatment ofage-related cataracts. This molecule protects the crystalline lens fromoxidative stress-induced damage, and in a recent clinical trial it was shown toproduce an effective, safe and long-term improvement in sight. Whenadministered topically to the eye in the form of Can-C, N-acetylcarnosinefunctions as a time-release prodrug form of L-carnosine resistant to hydrolysiswith carnosinase. N-acetylcarnosine has potential as an in vivo universalantioxidant because of its ability to protect against oxidative stress in thelipid phase of biological cellular membranes and in the aqueous environment bya gradual intraocular turnover into L-carnosine. In our study the clinicaleffects of a topical solution of N-acetylcarnosine (Can-C) on lens opacitieswere examined in patients with cataracts and in canines with age-relatedcataracts. These data showed that N-acetylcarnosine is effective in themanagement of age-related cataract reversal and prevention both in human and incanine eyes.

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12. Stvolinsky SL, Kukley ML,Dobrota D, Matejovicova M, Tkac I and Boldyrev AA (1999). Carnosine: anendogenous neuroprotector in the ischemic brain. Cell Mol Neurobiol. 19: 45-56.Institute of Neurology, Russian Academy of Medical Sciences, Moscow, Russia. 1.The biological effects of carnosine, a natural hydrophilic neuropeptide, on thereactive oxygen species (ROS) pathological generation are reviewed. 2. Wedescribe direct antioxidant action observed in the in vitro experiments. 3.Carnosine was found to effect metabolism indirectly. These effects arereflected in ROS turnover regulation and lipid peroxidation (LPO) processes. 4.During brain ischemia carnosine acts as a neuroprotector, contributing tobetter cerebral blood flow restoration, electroencephalography (EEG)normalization, decreased lactate accumulation, and enzymatic protection againstROS. 5. The data presented demonstrate that carnosine is a specific regulatorof essential metabolic pathways in neurons supporting brain homeostasis underunfavorable conditions.

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13. Kang JH and Kim KS (2003).Enhanced oligomerization of the alpha-synuclein mutant by the Cu,Zn-superoxidedismutase and hydrogen peroxide system. Mol Cells. 15: 87-93. Department ofGenetic Engineering, Chongju University, Chongju 360-764, Korea.jhkang@chongju.ac.kr. The alpha-synuclein is a major component of Lewy bodiesthat are found in the brains of patients with Parkinson's disease (PD). Also,two point mutations in this protein, A53T and A30P, are associated with rarefamilial forms of the disease. We investigated whether there are differences inthe Cu,Zn-SOD and hydrogen peroxide system mediated-protein modificationbetween the wild-type and mutant alpha-synucleins. When alpha-synuclein was incubatedwith both Cu,Zn-SOD and H2O2, then the amount of A53T mutant oligomerizationincreased relative to that of the wild-type protein. This process was inhibitedby radical scavenger, spin-trapping agent, and copper chelator. These resultssuggest that the oligomerization of alpha-synuclein is mediated by thegeneration of the hydroxyl radical through the metal-catalyzed reaction. Thedityrosine formation of the A53T mutant protein was enhanced relative to thatof the wild-type protein. Antioxidant molecules, carnosine, and anserineeffectively inhibited the wild-type and mutant proteins' oligomerization.Therefore, these compounds may be explored as potential therapeutic agents forPD patients. The present experiments, in part, may provide an explanation forthe association between PD and the alpha-synuclein mutant.

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14. Thiel R and Fowkes SW (2005).Can cognitive deterioration associated with Down syndrome be reduced? MedHypotheses. 64: 524-32. Center for Natural Health Research, DownSyndrome-Epilepsy Foundation, 1248 E. Grand Avenue, Suite A, Arroyo Grande, CA93420, USA. Individuals with Down syndrome have signs of possible brain damageprior to birth. In addition to slowed and reduced mental development, they aremuch more likely to have cognitive deterioration and develop dementia at anearlier age than individuals without Down syndrome. Some of the cognitiveimpairments are likely due to post-natal hydrogen peroxide-mediated oxidativestress caused by overexpression of the superoxide dismutase (SOD-1) gene, whichis located on the triplicated 21st chromosome and known to be 50%overexpressed. However, some of this disability may also be due to earlyaccumulation of advanced protein glycation end-products, which may play anadverse role in prenatal and postnatal brain development. This paper suggeststhat essential nutrients such as folate, vitamin B6, vitamin C, vitamin E,selenium, and zinc, as well as alpha-lipoic acid and carnosine may possibly bepartially preventive. Acetyl-l-carnitine, aminoguanidine, cysteine, andN-acetylcysteine are also discussed, but have possible safety concerns for thispopulation. This paper hypothesizes that nutritional factors begun prenatally,in early infancy, or later may prevent or delay the onset of dementia in the Downsyndrome population. Further examination of these data may provide insightsinto nutritional, metabolic and pharmacological treatments for dementias ofmany kinds. As the Down syndrome population may be the largest identifiablegroup at increased risk for developing dementia, clinical research to verifythe possible validity of the prophylactic use of anti-glycation nutrientsshould be performed. Such research might also help those with glycationcomplications associated with diabetes or Alzheimer's.

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15. Petroff OA, Hyder F, RothmanDL and Mattson RH (2001). Topiramate rapidly raises brain GABA in epilepsypatients. Epilepsia. 42: 543-8. Department of Neurology, Yale University, NewHaven, Connecticut 06520-8018, USA. PURPOSE: The short- and long-term pharmacodynamiceffects of topiramate (TPM) on brain gammay-aminobutyric acid (GABA) metabolismwere studied in patients with complex partial seizures. METHODS: In vivomeasurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-ccvolume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magneticresonance spectrometer and an 8-cm surface coil. Fifteen patients (four men)were studied serially after the first, oral dose (100 mg) of TPM. RESULTS: Thefirst dose of TPM increased brain GABA within 1 h. Within 4 h, GABA wasincreased by 0.9 mM (95% CI, 0.7-1.1). Brain GABA remained elevated for > or=24 h. Pyrrolidinone and homocarnosine increased slowly during the first day.Daily TPM therapy (median, 300 mg; range, 200-500) increased GABA (0.3 mM; 95%CI, 0.1-0.5), homocarnosine (0.4 mM; 95% CI, 0.3-0.5), and pyrrolidinone (0.15mM; 95% CI, 0.10-0.19), compared with levels before TPM. There was no doseresponse evident with daily TPM doses of 200-500 mg. CONCLUSIONS: TPM promptlyelevates brain GABA and presumably offers partial protection against furtherseizures within hours of the first oral dose. Patients may expect to experiencethe effects of increased homocarnosine and pyrrolidinone within 24 h.

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16. Petroff OA, Hyder F, RothmanDL and Mattson RH (2001). Homocarnosine and seizure control in juvenilemyoclonic epilepsy and complex partial seizures. Neurology. 56: 709-15.Department of Neurology, Yale University, New Haven, CT 06520-8018, USA.OBJECTIVE: To assess the relationship between seizure control andgamma-aminobutyric acid (GABA), homocarnosine, and pyrrolidinone levels in thevisual cortex of patients with epilepsy taking valproate or lamotrigine.Previous studies suggested that poor seizure control was associated with low GABAand homocarnosine levels. METHODS: In vivo measurements of GABA, homocarnosine,and pyrrolidinone were made in a 14-cm(3) volume of the occipital cortex using(1)H spectroscopy with a 2.1-Tesla MR spectrometer and an 8-cm surface coil.Twenty-six adults (eight men) taking valproate or lamotrigine were recruited;12 had complex partial seizures (CPS) and 14 had juvenile myoclonic epilepsy(JME). RESULTS: Median homocarnosine levels were normal for patients with JMEand below normal for patients with CPS. Better seizure control was associatedwith higher homocarnosine levels for both groups. Median GABA was below normalfor patients with JME, lower than for patients with CPS. Brain GABA was lowestin patients with JME even when seizure control was excellent. Pyrrolidinonelevels were above normal in almost all patients with JME. CONCLUSIONS: Low GABAlevels are associated with poor seizure control in patients with CPS, but notin JME. Higher homocarnosine levels are associated with better seizure control inboth types of epilepsy.

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17. Soliman K, El-Ansary A andMohamed AM (2001). Effect of carnosine administration on metabolic parametersin bilharzia-infected hamsters. Comp Biochem Physiol B Biochem Mol Biol. 129:157-64. Biochemistry Department, Faculty of Medicine, Cairo University, Cairo,Egypt. solimank2002@yahoo.com. Carnosine is a naturally occurring dipeptide(beta-alanyl-L-histidine) found in muscles, brain and other tissues. This studywas designed to test the ability of carnosine to offset metabolic disturbancesinduced by Schistosoma mansoni parasitism. Results indicate that parasiticinfection caused elevation of liver weight/body weight in S. mansoni-infectedhamsters, induced lipid peroxidation and reduced glycogen levels. Moreover,adenylate energy charge (AEC) and ATP/ADP and ATP/AMP concentration ratios weremarkedly lower in infected hamsters. Administration of carnosine (10 mg/day)for 15 days concurrent with infection effectively reduced worm burden and eggcount. Administration of carnosine 2 and 4 weeks post-exposure only partiallyameliorated the S. mansoni effects on metabolism. Carnosine treatment alsonormalized most of the parameters measured, including glycogen repletion, theantioxidant status and AEC. These finding support the use of carnosine forpossible intervention in schistosomiasis.

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18. Ferrari CK (2004). Functionalfoods, herbs and nutraceuticals: towards biochemical mechanisms of healthyaging. Biogerontology. 5: 275-89. Department of Nutrition, Faculty of PublicHealth, University of Sao Paulo, Av Dr. Arnaldo, 715, 2 andar, 01246-904, SaoPaulo (SP), Brazil. drcarlosferrari@hotmail.com. Aging is associated withmitochondrial dysfunctions, which trigger membrane leakage, release of reactivespecies from oxygen and nitrogen and subsequent induction of peroxidativereactions that result in biomolecules' damaging and releasing of metals withamplification of free radicals discharge. Free radicals induce neuronal celldeath increasing tissue loss, which could be associated with memory detriment.These pathological events are involved in cardiovascular, neurodegenerative andcarcinogenic processes. Dietary bioactive compounds from different functionalfoods, herbs and nutraceuticals (ginseng, ginkgo, nuts, grains, tomato, soy phytoestrogens,curcumin, melatonin, polyphenols, antioxidant vitamins, carnitine, carnosine,ubiquinone, etc.) can ameliorate or even prevent diseases. Protection fromchronic diseases of aging involves antioxidant activities, mitochondrialstabilizing functions, metal chelating activities, inhibition of apoptosis ofvital cells, and induction of cancer cell apoptosis. Functional foods andnutraceuticals constitute a great promise to improve health and preventaging-related chronic diseases.

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19. Hipkiss AR, Brownson C andCarrier MJ (2001). Carnosine, the anti-ageing, anti-oxidant dipeptide, mayreact with protein carbonyl groups. Mech Ageing Dev. 122: 1431-45. Division ofBiomolecular Sciences, GKT School of Biomedical Sciences, King's CollegeLondon, Guy's Campus, London Bridge, London SE1 1UL, UK.alan.hipkiss@kcl.ac.uk. Carnosine (beta-alanyl-L-histidine) is a physiologicaldipeptide which can delay ageing and rejuvenate senescent cultured humanfibroblasts. Carnosine's anti-oxidant, free radical- and metal ion-scavengingactivities cannot adequately explain these effects. Previous studies showedthat carnosine reacts with small carbonyl compounds (aldehydes and ketones) andprotects macromolecules against their cross-linking actions. Ageing isassociated with accumulation of carbonyl groups on proteins. We consider herewhether carnosine reacts with protein carbonyl groups. Our evidence indicatesthat carnosine can react non-enzymically with protein carbonyl groups, aprocess termed 'carnosinylation'. We propose that similar reactions could occurin cultured fibroblasts and in vivo. A preliminary experiment suggesting thatcarnosine is effective in vivo is presented; it suppressed diabetes-associatedincrease in blood pressure in fructose-fed rats, an observation consistent withcarnosine's anti-glycating actions. We speculate that: (i) carnosine's apparentanti-ageing actions result, partly, from its ability to react with carbonylgroups on glycated/oxidised proteins and other molecules; (ii) this reaction, termed'carnosinylation,' inhibits cross-linking of glycoxidised proteins to normalmacromolecules; and (iii) carnosinylation could affect the fate of glycoxidisedpolypeptides.

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20. Boldyrev AA, Yuneva MO,Sorokina EV, Kramarenko GG, Fedorova TN, Konovalova GG and Lankin VZ (2001).Antioxidant systems in tissues of senescence accelerated mice. Biochemistry(Mosc). 66: 1157-63. Department of Biochemistry, School of Biology, LomonosovMoscow State University, Moscow, 119899, Russia. aa_boldyrev@mail.ru.Significant decrease in the level of lipid antioxidants (measured from thekinetics of the induced chemiluminescence in brain homogenate) and of thehydrophilic antioxidant carnosine as well was observed in the brain of14-16-month-old mice of SAMP1 line, which is characterized by acceleratedaccumulation of senile features, in comparison with the control line SAMR1. Inthe brain of SAMP1 animals the activity of cytosolic Cu/Zn-containingsuperoxide dismutase (SOD) was reduced, while the activity of membrane-boundMn-SOD was at an extremely low level. The activity of glutathione-dependentenzymes (glutathione peroxidase, glutathione reductase, and glutathionetransferase) did not differ in the brain of SAMP1 and SAMR1 animals, andcatalase activity was similarly low in both cases. At the same time, excessconcentration of excitotoxic compounds, significantly exceeding that for thecontrol line, was determined in the brain and blood of SAMP1 animals. Theactivity of glutathione enzymes in liver and heart as well as the activity ofcytosolic Cu/Zn-SOD in liver did not differ in the two studied lines, while theactivity of erythrocyte glutathione peroxidase was slightly increased, and the activityof liver catalase and erythrocyte Cu/Zn-SOD was significantly decreased forSAMP1 compared with SAMR1. The results demonstrate that the accelerated ageingof SAMP1 animals is connected to a significant extent with the decreasedefficiency of the systems utilizing reactive oxygen species (ROS) in tissues.

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21. Stuerenburg HJ (2000). Theroles of carnosine in aging of skeletal muscle and in neuromuscular diseases.Biochemistry (Mosc). 65: 862-5. Neurological Department, University HospitalHamburg-Eppendorf, 20246 Hamburg, Germany. stuerenburg@uke.uni-hamburg.de.Skeletal muscles undergo specific alterations that are related to the agingprocess. The incidence of several neuromuscular diseases (e.g., amyotrophiclateral sclerosis (ALS), myasthenia gravis, polymyositis, drug-inducedmyopathies, late-onset mitochondrial myopathy) is age-related. The increasedsensitivity to disease of aging muscle represents an additional age-relatednegative influence in the presence of existing risk factors (such as a geneticpredisposition). The potential significance of carnosine lies on one hand inits possible influence on specific physiological changes in muscle associatedwith the aging process, and on the other in its effect on oxidative stress andthe antioxidative system in specific neuromuscular diseases such as ALS orpolymyositis.

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22. Maynard LM, Boissonneault GA,Chow CK and Bruckner GG (2001). High levels of dietary carnosine are associatedwith increased concentrations of carnosine and histidine in rat soleus muscle.J Nutr. 131: 287-90. Department of Clinical Science/Division of ClinicalNutrition, University of Kentucky, Lexington, Kentucky 40506, USA.leah.maynard@wright.edu. The aims of this investigation were to: 1) determinethe effect of a moderately high dose of carnosine on muscle concentrations ofcarnosine, histidine and vitamin E at deficient, minimally adequate andsufficient levels of dietary vitamin E and 2) compare the effects of moderatelyhigh and pharmacological doses of carnosine on muscle concentrations ofcarnosine, histidine and vitamin E when dietary vitamin E is minimallyadequate. Muscle concentrations of carnosine, histidine and vitamin E weremeasured in the lateral gastrocnemius and red and white vastus lateralis;carnosine and histidine concentrations were also measured in soleus muscle.Male Sprague-Dawley rats (n = 12/group) were fed a basal vitamin E-deficientdiet supplemented with either 0, 0.001 or 0.01% vitamin E and 0, 0.1 or 1.8%carnosine. After 8 wk, 1.8% carnosine resulted in significant fivefoldincreases in carnosine and twofold increases in histidine in the soleus muscle(P < or = 0.05). Muscle vitamin E concentrations were not significantlyaffected by dietary carnosine. Thus, very high levels of dietary carnosine areassociated with increases in carnosine and histidine concentrations in ratsoleus muscle.

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23. Tanida M, Niijima A, FukudaY, Sawai H, Tsuruoka N, Shen J, Yamada S, Kiso Y and Nagai K (2005).Dose-dependent effects of L-carnosine on the renal sympathetic nerve and bloodpressure in urethane-anesthetized rats. Am J Physiol Regul Integr Comp Physiol.288: R447-55. Division of Protein Metabolism, Institute for Protein Research,Osaka University, Osaka, Japan. The physiological function of L-carnosine (beta-alanyl-L-histidine)synthesized in mammalian muscles has been unclear. Previously, we observed thatintravenous (i.v.) injection of L-carnosine suppressed renal sympathetic nerveactivity (RSNA) in urethane-anesthetized rats, and L-carnosine administered viathe diet inhibited the elevation of blood pressure (BP) in deoxycorticosteroneacetate salt hypertensive rats. To identify the mechanism, we examined effectsof i.v. or intralateral cerebral ventricular (l.c.v.) injection of variousdoses of L-carnosine on RSNA and BP in urethane-anesthetized rats. Lower doses(1 microg i.v.; 0.01 microg l.c.v.) of L-carnosine significantly suppressedRSNA and BP, whereas higher doses (100 microg i.v.; 10 microg l.c.v.) elevatedRSNA and BP. Furthermore, we examined effects of antagonists of histaminergic(H1 and H3) receptors on L-carnosine-induced effects. When peripherally andcentrally given, thioperamide, an H3 receptor antagonist, blocked RSNA and BPdecreases induced by the lower doses of peripheral L-carnosine, whereasdiphenhydramine, an H1 receptor antagonist, inhibited increases induced by thehigher doses of peripheral L-carnosine. Moreover, bilateral lesions of thehypothalamic suprachiasmatic nucleus eliminated both effects on RSNA and BPinduced by the lower (1 microg) and higher (100 microg) doses of peripheralL-carnosine. These findings suggest that low-dose L-carnosine suppresses andhigh-dose L-carnosine stimulates RSNA and BP, that the suprachiasmatic nucleusand histaminergic nerve are involved in the activities, and that L-carnosineacts in the brain and possibly other organs.

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24. Tomonaga S, Tachibana T,Takagi T, Saito ES, Zhang R, Denbow DM and Furuse M (2004). Effect of centraladministration of carnosine and its constituents on behaviors in chicks. BrainRes Bull. 63: 75-82. Laboratory of Advanced Animal and Marine Bioresources,Graduate School of Bioresource and Bioenvironmental Science, Kyushu University,Fukuoka 812-8581, Japan. Even though their contents in the brain are high, thefunction of brain carnosine and its constituents has not been clarified. Bothcarnosine and anserine inhibited food intake in a dose dependent fashion wheninjected intracerebroventricularly. The constituents of carnosine, beta-alanine(beta-Ala) and l-histidine (His), also inhibited food intake, but their effectswere weaker than carnosine itself. Co-administration with beta-Ala and Hisinhibited food intake similar to carnosine, but also altered other behaviors.Injection of carnosine induced hyperactivity and increased plasmacorticosterone level, whereas beta-Ala plus His induced hypoactivity manifestedas sleep-like behavior. This later effect seemed to be derived from beta-Ala,not His. These results suggest that central carnosine may act in the brain ofchicks to regulate brain function and/or behavior in a manner different fromits constituents.

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25. Dupin AM, Boldyrev AA,Arkhipenko Iu V and Kagan VE (1984). [Carnosine protection of Ca2+ transportagainst damage induced by lipid peroxidation]. Biull Eksp Biol Med. 98: 186-8.The authors studied the protective action of carnosine on sarcoplasmicreticulum (SR) membranes from frog skeletal muscles destroyed by ascorbicacid-dependent lipid peroxidation (LPO). It was demonstrated that addition ofcarnosine to the incubation medium at a concentration of 25 mM sharplydecelerated inactivation of Ca-ATPase of SR membranes, maintaining at the sametime the coupling of hydrolysing and transport functions of the Ca-pump. Whengiven at the same concentration carnosine inhibited the accumulation of LPOproducts reacting with 2-thiobarbituric acid. This effect of carnosine wasfollowed by its utilization.

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26. Krichevskaia AA, BondarenkoTI, Makletsova MG and Mikhaleva, II (1985). [Protective effect of theneuropeptide homocarnosine in hyperbaric oxygenation]. Vopr Med Khim. 31: 75-9.Homocarnosine, at a dose of 10 mg per 100 g of animal body mass administeredintraperitoneally within 15 min before hyperbaric oxygenation with 0.7 MPa ofoxygen, exhibited a protective effect. After administration of the neuropeptideinto animals before hyperbaric oxygenation a latent period of oxygenconvulsions was increased; content of homocarnosine and gamma-aminobutyric acid(GABA) was maintained at the level found in brain of control animals. In braintissue of unprotected animals content of homocarnosine and GABA was decreaseddue to the oxygen treatment. GABA was less effective, its protective doseexceeded 10-fold the dose of homocarnosine. The neuropeptide exhibitedantioxidant properties in reactions of lipid peroxidation under normalconditions and in hyperbaric oxygenation in vitro. The antioxidant activity ofGABA was distinctly lower as compared with homocarnosine.

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27. Boldyrev AA (1986).[Biological role of histidine-containing dipeptides]. Biokhimiia. 51: 1930-43.The biological role of histidine-containing dipeptides is reviewed. The role ofcarnosine and anserine in muscle function is discussed from the evolutionaryviewpoint. Evidence on the antioxidative effect of carnosine and its protectionof biological membranes against lipid peroxidation-induced damages ispresented. The effects of presently known natural antioxidative agents andcarnosine on lipid peroxidation are compared. Carnosine has been shown to be amore universal protector of membranes as compared to free radical scavengers.

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28. Boldyrev AA, Dupin AM, BuninA, Babizhaev MA and Severin SE (1987). The antioxidative properties ofcarnosine, a natural histidine containing dipeptide. Biochem Int. 15: 1105-13.Department of Biochemistry, Moscow State University, USSR. The experimentalresults suggest that the antioxidative function of carnosine is one of the mostimportant manifestations of its biological role. The ability of carnosine tointeract directly with lipid peroxidation products was demonstrated. Theeffects of carnosine on partial restoration of lens transparency in dog eyeswith senile cataract which is known to be caused by lipid peroxidation weredemonstrated "in vitro" and "in vivo".

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29. Boldyrev AA, Dupin AM, PindelEV and Severin SE (1988). Antioxidative properties of histidine-containingdipeptides from skeletal muscles of vertebrates. Comp Biochem Physiol B. 89:245-50. Department of Biochemistry, School of Biology, Moscow State University,U.S.S.R. 1. Ascorbate-dependent peroxidation of lipid components of biologicalmembranes is inhibited by the natural histidine-containing dipeptides,carnosine and anserine, used at physiological concentrations. 2. Carnosine andanserine exhibit an equal antioxidative activity, whereas the preventing effectof homocarnosine is manifested only at low concentrations of oxidized lipidmaterial. 3. The inhibiting effect of the dipeptides is enhanced either by therise in the dipeptide concentration or by the decrease in the level of membranecomponents. 4. Addition of the dipeptides results in a marked decrease in thelevel of primary molecular products of lipid peroxidation. 5. In this case theoptical spectrum of primary molecular products of polyunsaturated fatty acidschanges significantly.

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30. Boldyrev AA, Dupin AM,Siambela M and Stvolinsky SL (1988). The level of natural antioxidantglutathione and histidine-containing dipeptides in skeletal muscles ofdeveloping chick embryos. Comp Biochem Physiol B. 89: 197-200. Department ofBiochemistry, School of Biology, Moscow State University, U.S.S.R. 1. Thelevels of glutathione and histidine-containing dipeptides in skeletal muscleschange in different ways during ontogenesis. 2. The glutathione content inskeletal muscles increases between the 9th and 18th days ofembryongenesis--from 0.5 to 2.0 mumol/g of tissue wet wt and then drops to zeroin 3-week-old chickens. 3. The level of histidine-containing dipeptidesincreases throughout the observation period beginning with their appearance onthe 14th day in leg muscles and on the 15th day in breast muscles of chickenembryos up to the 21st postnatal day. 4. There is a negative correlationbetween the antioxidative systems of glutathione and histidine-containingdipeptides in muscle tissue, i.e. dipeptide-rich tissues contain little or noglutathione and vice versa.

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31. Boldyrev AA, Dupin AM,Batrukova MA, Bavykina NI, Korshunova GA and Shvachkin Yu P (1989). Acomparative study of synthetic carnosine analogs as antioxidants. Comp BiochemPhysiol B. 94: 237-40. School of Biology, M. V. Lomonosov Moscow StateUniversity, USSR. 1. The antioxidative activity of carnosine and 16 relatedcompounds, both synthetic and natural, was determined. 2. The antioxidativeeffect was estimated by the ability of the dipeptides to prevent MDAaccumulation in the course of LPO induced in rabbit sarcoplasmic reticulummembranes by the Fe2+ ascorbate system. 3. It was found that the antioxidativeeffect comparable to that of carnosine was exerted by water-soluble(cyclo-L-histidyl-L-proline) and alcohol-soluble(cyclo-L-histidyl-L-phenilalanine) dipeptides as well as by the histidine-freecyclodipeptides (cyclo-L-tyrosyl-L-proline). 4. However, in contrast to itssynthetic analogs, carnosine not only inhibited the LPO, but also diminishedthe level of products accumulated during membrane lipid peroxidation.

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32. Boldyrev AA and Severin SE(1990). The histidine-containing dipeptides, carnosine and anserine:distribution, properties and biological significance. Adv Enzyme Regul. 30:175-94. Department of Biochemistry, Moscow State University, U.S.S.R. Thebiological significance of histidine-containing dipeptides discovered withinthe composition of nitrogenous extracts of skeletal muscles at the beginning ofthis century is still open to question. The present investigation is concernedwith the analysis of distribution and metabolism of these compounds withspecial reference to their effects on functional activity of membrane-linkedenzymatic systems, stability of cellular membranes, muscle contractibility,etc. The proposed hypothesis on stabilizing properties of carnosine and relatedsubstances on biological membranes is based on the ability of the dipeptides tointeract with lipid peroxidation products and active oxygen species and toprevent membrane damage. This remarkable antioxidative effect of carnosinereflects the high therapeutic value of this compound as an anti-inflammatorydrug and a prominent tool in wound healing.

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33. Guliaeva NV, Dupin AM, LevshinaIP, Obidin AB and Boldyrev AA (1989). [Carnosine prevents the activation offree-radical lipid oxidation during stress]. Biull Eksp Biol Med. 107: 144-7.Carnosine (beta-alanyl-L-histidine) injected to intact albino rats (20 mg/kgbody weight) induces depletion of lipid peroxidation (LPO) products in brainand blood serum, an increase of superoxide scavenging activity in brain andserum, decrease of cholesterol: phospholipid ratio and increase of easyoxidizable phospholipid portion in brain lipid extracts. After painful stress(footshock during 2 hours) LPO products are accumulated in brain and serum,cholesterol: phospholipid ratio increases and the portion of easy oxidizablephospholipids decreases. Carnosine given before stress prevents LPO activation.Effects of carnosine and stress are not additive: LPO inhibition induced bycarnosine is much more in rats subjected to stress.

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34. Kohen R, Yamamoto Y, Cundy KCand Ames BN (1988). Antioxidant activity of carnosine, homocarnosine, andanserine present in muscle and brain. Proc Natl Acad Sci U S A. 85: 3175-9.Department of Biochemistry, University of California, Berkeley 94720.Carnosine, homocarnosine, and anserine are present in high concentrations inthe muscle and brain of many animals and humans. However, their exact functionis not clear. The antioxidant activity of these compounds has been examined bytesting their peroxyl radical-trapping ability at physiological concentrations.Carnosine, homocarnosine, anserine, and other histidine derivatives all showedantioxidant activity. All of these compounds showing peroxyl radical-trappingactivity were also electrochemically active as reducing agents in cyclic voltammetricmeasurements. Furthermore, carnosine inhibited the oxidative hydroxylation ofdeoxyguanosine induced by ascorbic acid and copper ions. Other roles ofcarnosine, such as chelation of metal ions, quenching of singlet oxygen, andbinding of hydroperoxides, are also discussed. The data suggest a role forthese histidine-related compounds as endogenous antioxidants in brain andmuscle.

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35. Aruoma OI, Laughton MJ andHalliwell B (1989). Carnosine, homocarnosine and anserine: could they act asantioxidants in vivo? Biochem J. 264: 863-9. Department of Biochemistry,University of London King's College, U.K. Carnosine, homocarnosine and anserinehave been proposed to act as antioxidants in vivo. Our studies show that allthree compounds are good scavengers of the hydroxyl radical (.OH) but that noneof them can react with superoxide radical, hydrogen peroxide or hypochlorousacid at biologically significant rates. None of them can bind iron ions in waysthat interfere with 'site-specific' iron-dependent radical damage to the sugardeoxyribose, nor can they restrict the availability of Cu2+ to phenanthroline.Homocarnosine has no effect on iron ion-dependent lipid peroxidation; carnosineand anserine have weak inhibitory effects when used at high concentrations insome (but not all) assay systems. However, the ability of these compounds tointerfere with a commonly used version of the thiobarbituric acid (TBA) testmay have led to an overestimate of their ability to inhibit lipid peroxidationin some previous studies. By contrast, histidine stimulated iron ion-dependentlipid peroxidation. It is concluded that, because of the high concentrationspresent in vivo, carnosine and anserine could conceivably act as physiologicalantioxidants by scavenging .OH, but that they do not have a broad spectrum ofantioxidant activity, and their ability to inhibit lipid peroxidation is notwell established. It may be that they have a function other than antioxidantprotection (e.g. buffering), but that they are safer to accumulate thanhistidine, which has a marked pro-oxidant action upon iron ion-dependent lipidperoxidation. The inability of homocarnosine to react with HOCl, interfere withthe TBA test or affect lipid peroxidation systems in the same way as carnosineis surprising in view of the apparent structural similarity between these twomolecules.

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36. Babizhayev MA, Seguin MC,Gueyne J, Evstigneeva RP, Ageyeva EA and Zheltukhina GA (1994). L-carnosine(beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as naturalantioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities.Biochem J. 304 ( Pt 2): 509-16. Moscow Helmholtz Research Institute of EyeDiseases, Russia. Carnosine (beta-alanyl-L-histidine) and carcinine(beta-alanylhistamine) are natural imidazole-containing compounds found in thenon-protein fraction of mammalian tissues. Carcinine was synthesized by anoriginal procedure and characterized. Both carnosine and carcinine (10-25 mM)are capable of inhibiting the catalysis of linoleic acid andphosphatidylcholine liposomal peroxidation (LPO) by the O2(-.)-dependentiron-ascorbate and lipid-peroxyl-radical-generating linoleic acid13-monohydroperoxide (LOOH)-activated haemoglobin systems, as measured bythiobarbituric-acid-reactive substance. Carcinine and carnosine are goodscavengers of OH. radicals, as detected by iron-dependent radical damage to thesugar deoxyribose. This suggests that carnosine and carcinine are able toscavenge free radicals or donate hydrogen ions. The iodometric, conjugateddiene and t.l.c. assessments of lipid hydroperoxides (13-monohydroperoxidelinoleic acid and phosphatidylcholine hydroperoxide) showed their efficientreduction and deactivation by carnosine and carcinine (10-25 mM) in theliberated and bound-to-artificial-bilayer states. This suggests that theperoxidase activity exceeded that susceptible to direct reduction withglutathione peroxidase. Imidazole, solutions of beta-alanine, or their mixtureswith peptide moieties did not show antioxidant potential. Free L-histidine andespecially histamine stimulated iron (II) salt-dependent LPO. Due to thecombination of weak metal chelating (abolished by EDTA), OH. and lipid peroxylradicals scavenging, reducing activities to liberated fatty acid and phospholipidhydroperoxides, carnosine and carcinine appear to be physiological antioxidantsable to efficiently protect the lipid phase of biological membranes and aqueousenvironments.

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37. Babizhayev MA and Costa EB(1994). Lipid peroxide and reactive oxygen species generating systems of thecrystalline lens. Biochim Biophys Acta. 1225: 326-37. Moscow Helmholtz ResearchInstitute of Eye Diseases, Russia. Lipid peroxidation (LPO) could be one of themechanisms of cataractogenesis, initiated by enhanced production of oxygen freeradicals in the eye fluids and tissues and impaired enzymatic and non-enzymaticdefences of the lens. The increased concentrations of primary molecular LPOproducts (diene conjugates, lipid hydroperoxides) and end fluorescent LPOproducts were detected in the lipid moiety of the aqueous humor samplesobtained from patients with cataract as compared to normal donors. Isolatedhuman transparent and cataractous lenses and normal mouse and rabbit lenseswere incubated with liposomes in organ culture in the presence and absence ofLPO inhibitors, free radical scavengers and enzymes (catalase, superoxidedismutase (SOD)) in order to examine the potential of the lenses to induce LPOin the surrounding medium. LPO assayed spectrophotometrically were diene andtriene conjugates, and malonaldehydes (MDA) were determined as thiobarbituricacid-reactive material. A chemiluminescence detection catalysed by peroxidasewas used to measure H2O2 and O2-. was assayed spectrophotometrically usingcytochrome C reduction. The level of lipid peroxides in liposomes wassignificantly (2.5-4.5-fold) higher after 3 h of incubation of the transparentlenses (or the lenses at the initial stage of cataract) than after the propertime of incubation of human mature cataractous lenses and virtually nooxidation of liposomes was detected in the absence of the lens. LPO in thissystem was decreased in the presence of free radical scavengers and enzymesthat degrade H2O2 (EDTA, SOD, L-carnosine, chelated iron and catalase). The mosteffective agent was EDTA which chelates the free metal cations required togenerate O2-. radicals that initiate the free radical process culminating inLPO. Lenses generated more H2O2 into the medium in the presence of exogenousascorbate. Release of the oxidants, (O2-., H2O2, OH. and lipid hydroperoxides)by the intact lenses in the absence of respiratory inhibitors indicates thatthese metabolites are normal physiological products inversely related to thelens life-span potential (maturity of cataract) generated, probably, throughthe metal-ion catalysed redox-coupled pro-oxidant activation of the lensreductants (ascorbic acid, glutathione).

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38. Gorbunov NV and Erin AN(1991). [Mechanism of antioxidant action of carnosine]. Biull Eksp Biol Med.111: 477-8. The comparative study of the antiradical activity of carnosine andvitamin C was carried out by the means of the evaluation of quenching of ESRsignals of 2,2-diphenyl-1-picrylhydrazyl (DFPH) and semiquinone radical ofalpha-tocopherol. It was shown that carnosine is not able to quench the ESRsignals of the stable radical of DFPH and semiquinone radical ofalpha-tocopherol. It permits to conclude that: a) carnosine does not interactdirectly with highly active free radicals; b) carnosine is unable to regeneratethe radical of alpha-tocopherol to form the antiradical synergistic couple. Thedata obtained are consistent with the idea that there is a difference betweenon the antioxidant mechanism action of vitamin C and carnosine due to thedifference in the antiradical activity of these compounds.

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39. Kohen R, Misgav R andGinsburg I (1991). The SOD like activity of copper:carnosine, copper:anserineand copper:homocarnosine complexes. Free Radic Res Commun. 12-13 Pt 1: 179-85.Department of Pharmacy, Hebrew University of Jerusalem, Hadasaah MedicalCenter, Israel. Carnosine, anserine and homocarnosine are natural compoundswhich are present in high concentrations (2-20 mM) in skeletal muscles andbrain of many vertebrates. We have demonstrated in a previous work that thesecompounds can act as antioxidants, a result of their ability to scavengeperoxyl radicals, singlet oxygen and hydroxyl radicals. Carnosine and itsanalogues have been shown to be efficient chelating agents for copper and othertransition metals. Since human skeletal muscle contains one-third of the totalcopper in the body (20-47 mmol/kg) and the concentration of carnosine in thistissue is relatively high, the complex of carnosine:copper may be of biologicalimportance. We have studied the ability of the copper:carnosine (and othercarnosine derivatives) complexes to act as superoxide dismutase. The resultsindicate that the complex of copper:carnosine can dismute superoxide radicalsreleased by neutrophils treated with PMA in an analogous mechanism to otheramino acids and copper complexes. Copper:anserine failed to dismute superoxideradicals and copper:homocarnosine complex was efficient when the cells weretreated with PMA or with histone-opsonized streptococci and cytochalasine B. Thepossible role of these compounds to act as physiological antioxidants thatpossess superoxide dismutase activity is discussed.

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40. Salim-Hanna M, Lissi E andVidela LA (1991). Free radical scavenging activity of carnosine. Free Radic ResCommun. 14: 263-70. Department of Chemistry, Faculty of Science, University ofSantiago, Chile. The capacity of carnosine to decrease free radical-induceddamage was evaluated using the oxidation of brain homogenates, the2,2'-azobis-2-amidino propane-induced oxidation of erythrocyte ghost membranes,the radiation induced inactivation of horseradish peroxidase and the2,2'-azobis-2-amidino propane-induced inactivation of lysozyme. Carnosineaddition up to 17 mM did not produce any significant protection in either lipidperoxidation system, as assayed by the oxygen uptake rate. Carnosine additionreduces the intensity of the visible luminescence emitted, apparently due to adark decomposition of the luminescent intermediates. Carnosine additionprotects horseradish peroxidase and lysozyme from free radical mediatedinactivation. The mean carnosine concentrations required to inhibit theinactivation rates by 50% were 0.13 mM and 0.6 mM for horseradish peroxidaseand lysozyme, respectively.

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41. MacFarlane N, McMurray J,O'Dowd JJ, Dargie HJ and Miller DJ (1991). Synergism of histidyl dipeptides asantioxidants. J Mol Cell Cardiol. 23: 1205-7. Institute of Physiology, GlasgowUniversity, UK. Histidyl dipeptides such as carnosine (beta-alanyl-L-histidine)and homocarnosine (gamma-amino-butyryl-L-histidine) are reported at millimolarconcentrations in several mammalian tissues (O'Dowd et al., 1988; House et al.,1989), but their precise physiological function, or functions, is uncertain.These compounds are known to be potent buffers at physiological pH (Davey,1960). They are also able to restore functional capacity to fatigued musclepreparations, stimulate some glycolytic enzymes and maintain coupling betweenmitochondrial oxidation and phosphorylation (Severin, 1964). Histidyldipeptides may also have antioxidant activity, though this finding iscontroversial. For example, Aruoma et al. have argued that these compounds,individually, are unable to scavenge superoxide (O2-.), hydrogen peroxide(H2O2) or hypochlorous acid (HOCl) at rates which could offer antioxidantprotection in vivo. Since there is a range of these histidyl dipeptides withinmammalian tissue we have investigated possible synergism between them inrespect of antioxidant activity. Our results show that combining histidine-containingcompounds at near physiological concentrations results in synergisticantioxidant activity.

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42. Yoshikawa T, Naito Y,Tanigawa T, Yoneta T, Yasuda M, Ueda S, Oyamada H and Kondo M (1991). Effect ofzinc-carnosine chelate compound (Z-103), a novel antioxidant, on acute gastricmucosal injury induced by ischemia-reperfusion in rats. Free Radic Res Commun.14: 289-96. First Department of Medicine, Kyoto Prefectural University ofMedicine, Japan. The protective effect of a novel synthetic zinc-carnosinechelate compound, zinc N-(3-aminopropionyl)-L-histidine (Z-103), on the gastricmucosal injury induced by ischemia-reperfusion was studied in rats. Ischemiaand reperfusion injury was produced on the rat stomach by applying a smallclamp to the celiac artery for 30 min and by removal of the clamp for 30 min.The decrease in the gastric mucosal blood flow was not influenced by thetreatment with Z-103. The increase in total area of the erosions on the stomachafter ischemia-reperfusion and the increase in lipid peroxides in the gastricmucosa were significantly inhibited by the oral administration of Z-103. Inaddition, Z-103 inhibited lipid peroxidation of rat brain homogenate and livermicrosome in vitro. These results suggest that the protective effect of Z-103against the aggravation of gastric mucosal injury induced byischemia-reperfusion may be due to its inhibitory effect on lipid peroxidation.

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43. Yoshikawa T, Naito Y,Tanigawa T, Yoneta T and Kondo M (1991). The antioxidant properties of a novelzinc-carnosine chelate compound, N-(3-aminopropionyl)-L-histidinato zinc.Biochim Biophys Acta. 1115: 15-22. First Department of Medicine, KyotoPrefectural University of Medicine, Japan. A zinc-carnosine chelate compound,Z-103, attenuates gastric mucosal injuries and inhibits the increase of lipidperoxide in the gastric mucosa induced by burn shock or ischemia-reperfusion.However, the exact mechanism of the antioxidative effect of Z-103 is not clear.The antioxidant properties of a novel anti-peptic ulcer agent Z-103 in vitrowere compared with those of zinc ion and L-carnosine. Z-103 scavengedsuperoxide anion radicals. Z-103 and ZnSO4, but not L-carnosine, inhibited thesuperoxide generation from polymorphonuclear leukocytes stimulated by opsonizedzymosan, and also inhibited the generation of hydroxyl radicals by the Fentonreaction. The increase of lipid peroxides produced by rat brain homogenates andliver microsomes was also inhibited by Z-103 and ZnSO4. These findings indicatethat the strong anti-ulcer and antioxidative actions of Z-103 in vivo are dueto a combination of these antioxidant actions in vitro.

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44. Guliaeva IV (1992).[Prospects for designing medicines based on carnosine (several newapplications)]. Biokhimiia. 57: 1398-403. The perspectives in application ofcarnosine, its analogs (histidine-containing dipeptides), and their derivativesas components of medicinal drugs are reviewed. These applications are based onantioxidative properties of carnosine and its analogs, their chelating activitytowards transient valency metals as well as on their specific neurotransmitterfunctions in the brain. Combination of carnosine with other antioxidants andthe use of copper or zinc complexes with histidine-containing dipeptides are consideredas perspective trends in the design of new drugs.

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45. Hartman Z and Hartman PE(1992). Copper and cobalt complexes of carnosine and anserine: production ofactive oxygen species and its enhancement by 2-mercaptoimidazoles. Chem BiolInteract. 84: 153-68. Department of Biology, Johns Hopkins University,Baltimore, Maryland 21218. Phosphate buffer solutions of two dipeptidesprevalent in striated muscle, L-carnosine (beta-alanyl-L-histidine) andL-anserine (beta-alanyl-L-1-methylhistidine), produce active oxygen species asmeasured by bleaching of N,N-dimethyl-4-nitrosoaniline (RNO). Activity isenhanced 5-14-fold in the presence of 2-mercaptoimidazoles such asergothioneine, carbimazole (3-methyl-2-mercaptoimidazole-1-carboxylate),methimazole (2-mercapto-1-methylimidazole) and 2-mercaptoimidazole but onlyslightly by thiourea and dimethylthiourea. Activity is proportional tocarnosine concentration and to mercaptoimidazole concentration at a fixedconcentration of the second component. A variety of imidazoles closely relatedto carnosine and anserine are inactive, even after addition of transition metalions. Activity is moderately increased above the pKa of the carnosine imidazolering (pH 7.2, 7.5 and 8.0) versus below the pKa (pH 6.5 and 6.8). Activity isslightly increased by addition of copper or cobalt ions but not by addition offerrous or ferric ions. Activity is decreased by Chelex 100 pretreatment ofphosphate buffer and stimulated when copper or cobalt ions are added to thechelated buffer but there is no significant stimulation by ferric ions.Catalase eliminates most activity but superoxide dismutase has little effect.We propose that metal-carnosine and metal-anserine complexes produce superoxideand also serve as superoxide dismutases with resultant accumulation of hydrogenperoxide. An unidentified radical produced from hydrogen peroxide subsequentlybleaches RNO. From the biological distributions of carnosine, anserine andergothioneine, we infer that deleterious effects are probably minimal undernormal physiological circumstances due to tissue and cellularcompartmentalization and to sequestration of these compounds and transitionmetal ions.

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46. Decker EA, Ivanov V, Zhu BZand Frei B (2001). Inhibition of low-density lipoprotein oxidation by carnosinehistidine. J Agric Food Chem. 49: 511-6. Department of Food Science, ChenowethLaboratory, University of Massachusetts, Amherst 01003, USA.edecker@foodsci.umass.edu. Carnosine is a beta-alanylhistidine dipeptide foundin skeletal muscle and nervous tissue that has been reported to possessantioxidant activity. Carnosine is a potential dietary antioxidant because itis absorbed into plasma intact. This research investigated the ability ofcarnosine to inhibit the oxidation of low-density lipoprotein (LDL) incomparison to its constituent amino acid, histidine. Carnosine (3 microM)inhibited Cu2+-promoted LDL (20 of protein/mL) oxidation at carnosine/copperratios as low as 1:1, as determined by loss of tryptophan fluorescence andformation of conjugated dienes. Carnosine (6 microM) lost its ability toinhibit conjugated diene formation and tryptophan oxidation after 2 and 4 h ofincubation, respectively, of LDL with 3 microM Cu2+. Compared to controls,histidine (3 microM) inhibited tryptophan oxidation and conjugated dieneformation 36 and 58%, respectively, compared to 21 and 0% for carnosine (3microM) after 3 h of oxidation. Histidine was more effective at inhibitingcopper-promoted formation of carbonyls on bovine serum albumin than carnosine,but carnosine was more effective at inhibiting copper-induced ascorbic acidoxidation than histidine. Neither carnosine nor histidine was a stronginhibitor of 2,2'-azobis(2-amidinopropane) dihydrochloride-promoted oxidationof LDL, indicating that their main antioxidant mechanism is through copperchelation.

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47. Trombley PQ, Horning MS andBlakemore LJ (2000). Interactions between carnosine and zinc and copper:implications for neuromodulation and neuroprotection. Biochemistry (Mosc). 65:807-16. Biomedical Research Facility, Department of Biological Science, FloridaState University, Tallahassee, Florida 32306-4340, USA. trombley@neuro.fsu.edu.This review examines interactions in the mammalian central nervous system (CNS)between carnosine and the endogenous transition metals zinc and copper.Although the relationship between these substances may be applicable to otherbrain regions, the focus is on the olfactory system where these substances mayhave special significance. Carnosine is not only highly concentrated in theolfactory system, but it is also contained in neurons (in contrast to gliacells in most of the brain) and has many features of a neurotransmitter.Whereas the function of carnosine in the CNS is not well understood, we reviewevidence that suggests that it may act as both a neuromodulator and aneuroprotective agent. Although zinc and/or copper are found in many neuronalpathways in the brain, the concentrations of zinc and copper in the olfactorybulb (the target of afferent input from sensory neurons in the nose) are amongthe highest in the CNS. Included in the multitude of physiological roles thatzinc and copper play in the CNS is modulation of neuronal excitability.However, zinc and copper also have been implicated in a variety of neurologicconditions including Alzheimer's disease, Parkinson's disease, stroke, andseizures. Here we review the modulatory effects that carnosine can have on zincand copper's abilities to influence neuronal excitability and to exertneurotoxic effects in the olfactory system. Other aspects of carnosine in theCNS are reviewed elsewhere in this issue.

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48. Trombley PQ, Horning MS andBlakemore LJ (1998). Carnosine modulates zinc and copper effects on amino acidreceptors and synaptic transmission. Neuroreport. 9: 3503-7. Department ofBiological Science, Florida State University, Tallahassee 32306-4340, USA.Carnosine is a dipeptide which is highly concentrated in mammalian olfactorysensory neurons along with zinc and/or copper, and glutamate. Althoughcarnosine has been proposed as a neurotransmitter or neuromodulator, nospecific function for carnosine has been identified. We used whole-cellcurrent- and voltage-clamp recording to examine the direct effects andneuromodulatory actions of carnosine on rat olfactory bulb neurons in primaryculture. Carnosine did not evoke a membrane current or affect currents evokedby glutamate, GABA or glycine. Copper and zinc inhibited NMDA and GABAreceptor-mediated currents and inhibited synaptic transmission. Carnosineprevented the actions of copper and reduced the effects of zinc. These resultssuggest that carnosine may indirectly influence neuronal excitability bymodulating the effects of zinc and copper.

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49. Severina IS and Busygina OG(1992). [The role of carnosine in the function of soluble of guanylatecyclase]. Biokhimiia. 57: 1330-6. The effect of carnosine on activation ofhuman platelet soluble guanylate cyclase has been studied in 105,000 gsupernatants and partially purified haem-deficient enzyme preparations. In the105,000 g supernatant carnosine (1 mM) inhibited (by about 70%) the enzymeactivation caused by sodium nitroprusside. In partially purified haem-deficientguanylate cyclase preparations the inhibition of enzyme activation by sodiumnitroprusside was 86%; further addition of carnosine had no effect on theenzyme activity. The strength of the activating effect of protoporphyrin IX onpartially purified haem-deficient guanylate cyclase did not differ from thatfor the 105,000 g supernatant; this stimulating effect did not change aftercarnosine addition. A conclusion is drawn that the inhibiting effect ofcarnosine on the ability of guanylate cyclase to be activated by sodiumnitroprusside is due to the dipeptide interaction with the guanylate cyclasehaem.

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50. Severina IS (1992). Solubleguanylate cyclase of platelets: function and regulation in normal andpathological states. Adv Enzyme Regul. 32: 35-56. Institute of Biological andMedical Chemistry, U.S.S.R. Academy of Medical Sciences, Moscow. Chromatographyof 105,000 x g supernatants of human and rat platelets on DEAE-celluloseyielded identical elution profiles containing 2 protein fractions (peaks I andII). Only peak II was found to possess guanylate cyclase activity. In thespectrum of the 105,000 x g supernatant of human platelets the absorptionmaximum was specified at 410 nm (the Soret band) which disappeared from thespectrum of the active protein fraction (peak II) but was detected in thenonactive fraction (peak I). The enzyme preparation was obtained in theheme-deficient form. In the experiments with rat platelets, the Soret band wasabsent from the corresponding spectra and the enzyme was not activated bysodium nitroprusside; i.e., in soluble guanylate cyclase of rat platelets,unlike the generally accepted notion, the heme is not a prosthetic group of theenzyme. It was shown that carnosine (beta-alanyl-L-histidine), a water-solubleantioxidant, inhibits guanylate cyclase activation by sodium nitroprusside.This inhibitory effect is caused by the interaction of carnosine with theguanylate cyclase heme and can be used for evaluating the degree of saturationof the enzyme with the heme. ADP-induced aggregation of human platelets(donors) is accompanied by a fall in the basal guanylate cyclase activity (withMg2+) and the enhancement of the enzyme stimulation with sodium nitroprusside,protoporphyrin IX, arachidonic acid and L-arginine with simultaneous cGMPelevation in platelets. A hypothetic scheme of the regulatory role of cGMP inplatelet aggregation is proposed. In the experiments with the acute myocardialischemia of rats, 15 min after the surgery a sharp fall in the plateletguanylate cyclase activity accompanied by a decrease in the enzyme activity inthe ischemic zone of the left ventricle of heart took place. The resultsprovided evidence of the high sensitivity of platelet guanylate cyclase topathological changes occurring in the myocardium at the earliest stages of thedevelopment of pathology.

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51. Severina IS (1994). [Solubleplatelet guanylate cyclase: significance of heme in regulating enzymaticactivity and the role of the enzyme in platelet aggregation]. Biokhimiia. 59:325-39. The lability of the bond between the protein molecule of human plateletguanylate cyclase and heme (the prosthetic group of the enzyme) has beenestablished. It was shown that soluble rat platelet guanylate cyclase exists inthese cells originally in a heme-deficient form. The data obtained suggest thatin contrast with the generally accepted view, heme is not the prosthetic groupof this enzyme. The water-soluble antioxidant carnosine(beta-alanyl-L-histidine) inhibits the guanylate cyclase activation by sodiumnitroprusside. This inhibitory effect is caused by carnosine interaction withthe guanylate cyclase heme and can be used for evaluating the degree of theheme deficiency of the enzyme. Analysis of the mechanism of guanylate cyclaseactivation by nitroso complexes of some transient metals (Fe, Co, Cr) differingin the degree of NO oxidation demonstrated that the essential requirement forthe realization of the hypotensive effect of these compounds is the activationof guanylate cyclase solely via a heme-dependent mechanism. The ADP-inducedaggregation of human platelets (donors) is accompanied by enhanced stimulationof guanylate cyclase by various activators with a simultaneous increase in theintraplatelet cGMP level. This stimulation occurs irrespective of theinvolvement of the guanylate cyclase heme in the mechanism of enzymeregulation. It is concluded that guanylate cyclase acts via a negative feedbackmechanism to control over platelet aggregation and mediates a signal todeaggregation. A hypothetic scheme for the regulatory role of cGMP in plateletaggregation is proposed.

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52. Severina IS (1995). [Solubleforms of guanylate cyclases: mechanism of activation by nitrogen oxide and rolein platelet aggregation]. Vestn Ross Akad Med Nauk. 41-6. The paper gives dataon the role of heme in the functioning soluble forms of guanylate cyclase (ofhuman platelets, rat heart and platelets), on the mechanism of nitrogenoxide-induced heme-dependent activation of enzymes, on the role of plateletguanylate cyclase in the regulation of human plateletaggregation/disaggregation and on the mechanism of antihypertensive andantiaggregatory action of enzyme activators. The instability of relationshipsof the protein molecule of human platelet guanylate cyclase and heme (regardedas a prosthetic group of the enzyme) results in heme loss during purificationof the enzyme and preparation of a heme-deficient agent having a drasticallyreduced ability to sodium nitroprusside activation. Soluble rat plateletguanylate cyclase was found to be present in these cell originally in aheme-deficient form, it was not activated by sodium nitroprusside and, unlikethe routine concepts, heme is not a moiety of this enzyme molecule. The watersoluble antioxidant carnosine (beta-alanyl-L-histidine) inhibits sodiumnitroprusside activation of guanylate cyclase by interacting with the heme ofenzyme of the NO group of nitroprusside and may be useful to reveal the degreeof htmt saturation of guanylate cyclase. The study of the mechanism ofactivation of guanylate cyclase by nitroso complexes of transition metals (Fe,Cr, Co) showed that their realization of antihypertensive effects required onlyheme-dependent activation of the enzyme. ADF-induced aggregation of human(donor) platelets is followed by stimulation of guanylate cyclase by variousactivators (despite heme involvement in the mechanism of activation) withconcurrent elevations of platelet cGMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

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53. Snimoniia GV, Tatishvili NI,Shiliia D, Bakanidze NT and Khachidze MV (1992). [The effect of carnosine onthe activity of Na,K,ATPase: prospective uses in clinical cardiology].Biokhimiia. 57: 1343-7. The effects of carnosine on erythrocyte membraneNa,K-ATPase and isolated enzyme in vitro as well as on membrane Na,K-ATPaseactivity and lipid peroxidation (LPO) in chronic heart failure (CHF) and acutemyocardial infarction (AMI) have been studied. CHF and AMI have been shown tobe associated with significant inhibition of the erythrocyte membraneNa,K-ATPase activity and LPO activation. Marked activation of erythrocytemembrane Na,K-ATPase by carnosine in comparison with the isolated enzyme hasbeen established. The ability of carnosine to induce Na,K-ATPase activation andprevent membrane depolarization indicates that the dipeptide may be a usefultool in the pathogenetic therapy of CFH and AMI.

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54. Kurella EG, Tyulina OV andBoldyrev AA (1999). Oxidative resistance of Na/K-ATPase. Cell Mol Neurobiol.19: 133-40. Laboratory of Clinical Neurochemistry, Institute of Neurology,Russian Academy of Medical Sciences, Moscow, Russia. 1. Oxidative modificationof Na/K-ATPase from brain and kidney has been studied. Brain enzyme has beenfound to be more sensitive than kidney enzyme to inhibition by both H2O2 andNaOCl. 2. The inhibition of Na/K-ATPase correlates well with the decrease in anumber of SH groups, suggesting that the latter belong mainly to ATPase proteinand are essential for the enzyme activity. We suggest that the differences inthe number, location, and accessibility of SH groups in Na/K-ATPase isozymespredict their oxidative stability. 3. The hydrophilic natural antioxidantcarnosine, the hydrophobic natural antioxidant alpha-tocopherol, and thesynthetic antioxidant ionol as well as the ferrous ion chelating agentdeferoxamine were found to protect Na/K-ATPase from oxidation by differentconcentrations of H2O2. The data suggest that these antioxidants are effectivedue to their ability to neutralize or to prevent formation of hydroxyl radicals.

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55. Prokopieva VD, Bohan NA,Johnson P, Abe H and Boldyrev AA (2000). Effects of carnosine and relatedcompounds on the stability and morphology of erythrocytes from alcoholics.Alcohol Alcohol. 35: 44-8. Mental Health Research Institute, Medical Academy ofSciences of Russia, Tomsk, Russia. The effects of carnosine and relatedcompounds on erythrocytes from alcoholics were studied. In their presence,erythrocytes showed an increased ability to resist haemolysis and showed a morenormal morphology, with carnosine and N-acetyl-carnosine being the mosteffective compounds. These beneficial properties of the dipeptides do notappear to be directly related to their antioxidant or buffering properties.

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56. Boldyrev AA (1993). Doescarnosine possess direct antioxidant activity? Int J Biochem. 25: 1101-7.Department of Biochemistry, Moscow State University, Russia. 1. A brief reviewof development of ideas of the antioxidant activity of carnosine and relatedcompounds is presented. 2. An analysis of the behaviour of carnosine indifferent models of free radical chain reactions shows that carnosine is apotent hydrophilic antioxidant of a direct non-enzymatic action. 3. It ischaracteristic of the higher activity of interaction with active hydroxylradical. 4. However the known biological effects of carnosine cannot beexplained only by its anti-oxidant properties.

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57. Boldyrev AA, Dudina EI, DupinAM, Chasovnikova LV, Formaziuk VE, Sergienko VI, Mal'tseva VV, Stvolinskii SL,Tiulina OV and Kurella EG (1993). [A comparison of the antioxidative activityof carnosine by using chemical and biological models]. Biull Eksp Biol Med.115: 607-9. The difference in the efficiency of carnosine as an antioxidant wasfound to be explained both by the source of carnosine and the specificity ofmodels used to achieve visualization. Commercial carnosine samples werecontaminated with compound (s) absorbing at 255-332 nm. At the same time theypossessed better antioxidant activity in the models with Fe2-inducedperoxidation process. In the case of chemical models for generation of activeforms of oxygen (several modifications of the Fenton reaction) or during burstof superoxide generation by leucocytes, the antioxidant effect of carnosine didnot depend of the source of the compound under study.

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58. Boldyrev AA, Koldobski A,Kurella E, Maltseva V and Stvolinski S (1993). Natural histidine-containingdipeptide carnosine as a potent hydrophilic antioxidant with membranestabilizing function. A biomedical aspect. Mol Chem Neuropathol. 19: 185-92.Department of Biochemistry, Moscow State University, Russia. A review on thedistribution and biological effects of carnosine and a hypothesis for itsbiological mechanisms of action are presented. Carnosine and its structural andfunctional relative, anserine, were found in skeletal muscles at the beginningof the century. Their effects on muscle-working capacity, on the stability ofmembrane-bound enzymes, as well as their potent immunomodulating property,could not be explained by their pH-buffering capacity or formation of thesecondary metabolites histidine and beta-alanine alone. This article suggeststhat the basis for the biological activities of carnosine and relativecompounds is their potent antioxidant and membrane-protecting activity. Theplausible chemical mechanism of this activity is discussed, and data regardingthe usage of carnosine as a drug for treatment of immunodeficiency aresummarized.

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59. Pavlov AR, Revina AA, DupinAM, Boldyrev AA and Yaropolov AI (1993). The mechanism of interaction ofcarnosine with superoxide radicals in water solutions. Biochim Biophys Acta.1157: 304-12. A.N. Bach Institute of Biochemistry, USSR Academy of Science,Moscow. The antiradical activity and the radiation stability of carnosine in watersolutions was studied by the pulse radiolysis technique with spectrophotometricregistration of absorbance. The transient spectra were recorded in the range245-670 nm during 2 x 10(-6)-20 s after the pulse using a flow system forcontinuous change and saturation of the samples by different gases. Also, thespectra of the stable products of radiolysis were studied. The results obtainedgive evidence that carnosine in water solutions in the presence of oxygenbehaves like a multifunctional antioxidant. Even at low concentrations,dipeptide forms a charge-transfer complex (Car ... O2-., lambda max = 265 nm)with the superoxide radical which changes the reactivity of O2-.. Theabsorbance band of the complex was shifted towards lower energy as compared to superoxideradical lambda max = 255 nm). The interaction of carnosine with OH-radicalsproceeding at very high rate and resulting in the formation of a stable productsuggested another type of dipeptide activity. The kinetic mechanism of theinteraction of carnosine with products of radiolysis of water in aerobicconditions is discussed.

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60. Hipkiss AR, Preston JE,Himswoth DT, Worthington VC and Abbot NJ (1997). Protective effects ofcarnosine against malondialdehyde-induced toxicity towards cultured rat brainendothelial cells. Neurosci Lett. 238: 135-8. Molecular Biology and BiophysicsGroup, King's College London, Strand, UK. Malondialdehyde (MDA) is adeleterious end-product of lipid peroxidation. The naturally-occurringdipeptide carnosine (beta-alanyl-L-histidine) is found in brain and innervatedtissues at concentrations up to 20 mM. Recent studies have shown that carnosinecan protect proteins against cross-linking mediated by aldehyde-containingsugars and glycolytic intermediates. Here we have investigated whethercarnosine is protective against malondialdehyde-induced protein damage andcellular toxicity. The results show that carnosine can (1) protect cultured ratbrain endothelial cells against MDA-induced toxicity and (2) inhibitMDA-induced protein modification (formation of cross-links and carbonylgroups).

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61. Hipkiss AR, Preston JE,Himsworth DT, Worthington VC, Keown M, Michaelis J, Lawrence J, Mateen A,Allende L, Eagles PA and Abbott NJ (1998). Pluripotent protective effects ofcarnosine, a naturally occurring dipeptide. Ann N Y Acad Sci. 854: 37-53.Molecular Biology and Biophysics Group, King's College London, Strand, UnitedKingdom. alan.hipkiss@kcl.ac.uk. Carnosine is a naturally occurring dipeptide(beta-alanyl-L-histidine) found in brain, innervated tissues, and the lens atconcentrations up to 20 mM in humans. In 1994 it was shown that carnosine coulddelay senescence of cultured human fibroblasts. Evidence will be presented tosuggest that carnosine, in addition to antioxidant and oxygen free-radicalscavenging activities, also reacts with deleterious aldehydes to protectsusceptible macromolecules. Our studies show that, in vitro, carnosine inhibitsnonenzymic glycosylation and cross-linking of proteins induced by reactivealdehydes (aldose and ketose sugars, certain triose glycolytic intermediatesand malondialdehyde (MDA), a lipid peroxidation product). Additionally we showthat carnosine inhibits formation of MDA-induced protein-associated advancedglycosylation end products (AGEs) and formation of DNA-protein cross-linksinduced by acetaldehyde and formaldehyde. At the cellular level 20 mM carnosineprotected cultured human fibroblasts and lymphocytes, CHO cells, and culturedrat brain endothelial cells against the toxic effects of formaldehyde,acetaldehyde and MDA, and AGEs formed by a lysine/deoxyribose mixture.Interestingly, carnosine protected cultured rat brain endothelial cells againstamyloid peptide toxicity. We propose that carnosine (which is remarkablynontoxic) or related structures should be explored for possible intervention inpathologies that involve deleterious aldehydes, for example, secondary diabeticcomplications, inflammatory phenomena, alcoholic liver disease, and possiblyAlzheimer's disease.

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62. Hipkiss AR and Chana H(1998). Carnosine protects proteins against methylglyoxal-mediatedmodifications. Biochem Biophys Res Commun. 248: 28-32. Molecular Biology andBiophysics Group, King's College London, United Kingdom.alan.hipkiss@kcl.ac.uk. Methylglyoxal (MG) (pyruvaldehyde) is an endogenousmetabolite which is present in increased concentrations in diabetics andimplicated in formation of advanced glycosylation end-products (AGEs) andsecondary diabetic complications. Carnosine (beta-alanyl-L-histidine) isnormally present in long-lived tissues at concentrations up to 20 mM in humans.Previous studies showed that carnosine can protect proteins againstaldehyde-containing cross-linking agents such as aldose and ketose hexose andtriose sugars, and malon-dialdehyde, the lipid peroxidation product. Here weexamine whether carnosine can protect protein exposed to MG. Our results showthat carnosine readily reacts with MG thereby inhibiting MG-mediated proteinmodification as revealed electrophoretically. We also investigated whethercarnosine could intervene when proteins were exposed to an MG-induced AGE (i.e.lysine incubated with MG). Our results show that carnosine can inhibit proteinmodification induced by a lysine-MG-AGE; this suggests a second interventionsite for carnosine and emphasizes its potential as a possible non-toxicmodulator of diabetic complications.

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63. Hipkiss AR (2000). Carnosineand protein carbonyl groups: a possible relationship. Biochemistry (Mosc). 65:771-8. Division of Biomolecular Sciences, GKT School of Biomedical Sciences,King's College London, London SE1 1UL, UK. alan.hipkiss@kcl.ac.uk. Carnosinehas been shown to react with low-molecular-weight aldehydes and ketones and hasbeen proposed as a naturally occurring anti-glycating agent. It is suggestedhere that carnosine can also react with ("carnosinylate") proteinsbearing carbonyl groups, and evidence supporting this idea is presented.Accumulation of protein carbonyl groups is associated with cellular ageingresulting from the effects of reactive oxygen species, reducing sugars, andother reactive aldehydes and ketones. Carnosine has been shown to delaysenescence and promote formation of a more juvenile phenotype in cultured humanfibroblasts. It is speculated that carnosine may intracellularly suppress thedeleterious effects of protein carbonyls by reacting with them to formprotein-carbonyl-carnosine adducts, i.e., "carnosinylated" proteins.Various fates of the carnosinylated proteins are discussed including formationof inert lipofuscin and proteolysis via proteosome and RAGE activities. It isproposed that the anti-ageing and rejuvenating effects of carnosine are morereadily explainable by its ability to react with protein carbonyls than itswell-documented antioxidant activity.

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64. Hipkiss AR (2004). Iscarnosine a naturally occurring suppressor of oxidative damage in olfactoryneurones? Rejuvenation Res. 7: 253-5. Centre for Experimental Therapeutics,William Harvey Research Institute, Barts' and the London School of Medicine andDentistry, London, United Kingdom. alanandjill@lineone.net. Ghanbari et al.recently showed that neurones from olfactory lobes of Alzheimer's patientsexhibit oxidative stress and it is well known that olfactory dysfunctionfrequently accompanies neurodegeneration. The olfactory lobe is normallyenriched in carnosine, a relatively non-toxic (and sometimes abundant)dipeptide which possesses functions (anti-oxidant, antiglycator, scavenger ofzinc and copper ions, toxic aldehydes and protein carbonyls) that are likely tosuppress oxidative stress. It is suggested that carnosine's therapeuticpotential should be explored in olfactory tissue. Should the peptide provebeneficial, olfactory carnosine administration could provide a direct route tocompromised tissue, avoiding serum carnosinases.

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65. Hyland P, Duggan O, HipkissA, Barnett C and Barnett Y (2000). The effects of carnosine on oxidative DNAdamage levels and in vitro lifespan in human peripheral blood derived CD4+Tcell clones. Mech Ageing Dev. 121: 203-15. Cancer and Ageing Research Group,University of Ulster, Northern Ireland BT52 1SA, Coleraine, UK. Carnosine(beta-alanyl-L-histidine), an abundant naturally-occurring dipeptide has beenshown to exhibit anti-ageing properties towards cultured cells, possibly due inpart to its antioxidant/free radical scavenging abilities. In this paper theresults of an investigation on the effects of carnosine, at the physiologicalconcentration of 20 mM, on oxidative DNA damage levels and in vitro lifespan inperipheral blood derived human CD4+ T cell clones are reported. Under theculture conditions used (20% O(2)) long term culture with carnosine resulted ina significant increase in the lifespan of a clone derived from a healthy youngsubject. No such extension was observed when a T cell clone from a healthy oldSENIEUR donor was similarly cultured. Culture with carnosine from the midpointof each clone's lifespan did not have any effect on longevity, independent ofdonor age. Oxidative DNA damage levels were measured in the clones at variouspoints in their lifespans. Carnosine acted as a weak antioxidant, with levelsof oxidative DNA damage being lower in T cells grown long term in the presenceof carnosine. The possibility that carnosine might confer anti-ageing effectsto T cells under physiological oxygen tensions would appear to be worthy offurther investigation.

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66. Tabakman R, Jiang H, LevineRA, Kohen R and Lazarovici P (2004). Apoptotic characteristics of cell deathand the neuroprotective effect of homocarnosine on pheochromocytoma PC12 cellsexposed to ischemia. J Neurosci Res. 75: 499-507. Department of Pharmacologyand Experimental Therapeutics, Faculty of Medicine, The Hebrew University ofJerusalem, Jerusalem, Israel. We recently improved an in vitro ischemic model,using PC12 neuronal cultures exposed to oxygen-glucose deprivation (OGD) for 3hr in a special device, followed by 18 hr of reoxygenation. The cell deathinduced in this ischemic model was evaluated by a series of markers: lactatedehydrogenase (LDH) release, caspase-3 activation, presence of cyclin D1,cytochrome c leakage from the mitochondria, BAX cellular redistribution,cleavage of poly (ADP-ribose) polymerase (PARP) to an 85-kDa apoptoticfragment, and DNA fragmentation. The OGD insult, in the absence ofreoxygenation, caused a strong activation of the mitogen-activated proteinkinase (MAPK) isoforms extracellular regulated kinase (ERK), c-Jun NH2-terminalkinase (JNK), and stress-activated protein kinase (SAPK), also known as p-38.The detection of apoptotic markers and activation of MAPKs during the ischemicinsult strongly suggest that apoptosis plays an important role in the PC12 celldeath. Homocarnosine, a neuroprotective histidine dipeptide, present in highconcentrations in the brain, was found to provide neuroprotection, as expressedby a 40% reduction in LDH release and caspase-3 activity at 1 mM. Homocarnosinereduced OGD activation of ERK 1, ERK 2, JNK 1, and JNK 2 by 40%, 46%, 55%, and30%, respectively. These results suggest that apoptosis is an importantcharacteristic of OGD-induced neuronal death and that antioxidants, such ashomocarnosine, may prevent OGD-induced neuronal death by inhibiting theapoptotic process and/or in relation to the differential attenuation ofactivity of MAPKs.

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67. Tabakman R, Lazarovici P andKohen R (2002). Neuroprotective effects of carnosine and homocarnosine onpheochromocytoma PC12 cells exposed to ischemia. J Neurosci Res. 68: 463-9.Department of Pharmacology and Experimental Therapeutics, Hebrew University ofJerusalem, Jerusalem, Israel. The development of neuroprotective drugs againstischemic insults is hampered by the lack of pharmacological in vitro models. Wedeveloped an ischemic model using PC12 cell cultures exposed tooxygen-glucose-deprivation (OGD) followed by reoxygenation (18 hr) underregular atmospheric oxygen level. The toxicity induced in this model, that ispartially caused by generation of reactive oxygen species (ROS), was measuredmorphologically as well as by the release of lactate dehydrogenase (LDH) andthe prostaglandin PGE(2) from the cells. Carnosine and homocarnosine, histidinedipeptides antioxidants, found in high concentration in the brain, have beensuggested to provide neuroprotection. Using the OGD model we found that 5 mMcarnosine and 1 mM homocarnosine provided maximal neuroprotection of about 50%against OGD insult. This neuroprotective effect was similar to that of a knownantioxidant, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol), and wasnot observed in a serum-deprivation toxicity model of PC12 cells, indicatingthat carnosine and homocarnosine may act as antioxidant-neuroprotective agentsin the brain. Our ischemic model may provide a useful tool for investigating themechanisms involved in the neuroprotection afforded by histidine dipeptides.

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68. Dolgikh VT and Rusakov VV(1992). [The use of carnosine for reducing the post-resuscitation damage to theheart following acute fatal blood loss]. Anesteziol Reanimatol. 56-9. Theexperiments on random-bred male rats have established that 4 and 6 min clinicaldeath of acute blood loss initiated lipid peroxidation processes (LPO), causingbiomembrane damage, enhanced adenyl nucleotide catabolism, activated glycolysisand glycogenolysis in the heart muscle and caused cardiac arrhythmias.Carnosine at a dose 25 mg/kg administered together with pumped blood enhancedresuscitation efficacy and reduced considerably lethality in the earlyrehabilitation period. A favourable effect of carnosine is associated with itsability to restrict LPO processes, inhibit glycolysis and glycogenolysis andcreate optimal conditions for the functioning of membrane-locatedlipid-dependent enzymes.

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69. Dolgikh VT, Rusakov VV,Korpacheva OV and Sudakova AN (1992). Pathogenesis and pharmacorrection ofearly postresuscitation cardiac arrhythmia. Resuscitation. 23: 179-91. Divisionof Pathophysiology, Medical Institute, Omsk, Russia. Effect of acute lethalblood loss on character and frequency of cardiac arrhythmias inpostresuscitation period has been studied. Experiments were carried out onmongrel male rats resuscitated after 4- and 6-min clinical death caused byacute blood loss. Electric cardiac instability was found in earlypostresuscitation period. Pacemaker migration, paroxysmal ventriculartachycardia, blockades and extrasystole that lead to ventricular fibrillationwere observed in 20 percent of cases. Supported by correlative analysis it hasbeen established that the main arrhythmogenic factors are abundance ofcatecholamines, free fatty acids, dienic conjugates, lactate and inhibition ofCa dependent ATPase. Antiarrhythmogenic effects of antihypoxant gutimin, thebeta-adrenoreceptor blocker inderal, antioxidant oxypiridin-6 were noticedafter their separate administration before clinical death. The same effect ofcarnosine and phosphocreatine administered during resuscitation also wasnoticed.

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70. Prokop'eva VD, Laptev BI andAfanas'ev SA (1992). [The protective effect of carnosine in hypoxia andreoxygenation of the isolated rat heart]. Biokhimiia. 57: 1389-92. The effectof carnosine (15 mM) on the contractile activity of isolated rat heartscontracting in an isotonic regime (37 degrees C at a 5 Hz stimulationfrequency) has been studied. Carnosine added to the perfusing solution had noeffect on the contractile activity either in hypoxia or during reoxygenationbut decreased it with a simultaneous increase in the coronary flow duringreoxygenation. Carnosine inhibited by 60% the lactate dehydrogenase releasefrom cardiac cells. A conclusion is drawn that the protective effect ofcarnosine is due to its membrane-stabilizing action which is implemented duringinhibition of peroxidation of membrane lipids.

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71. Rusakov VV and Dolgikh VT(1992). [Effects of carnosine on systemic hemodynamics and myocardialmetabolism in rats in the early postresuscitation period]. Biull Eksp Biol Med.113: 358-60. It was demonstrated in experiments on male rats that acute lethalblood loss and subsequent resuscitation after 4- and 6-min clinical deathinduce lipid peroxidation processes, decreased antioxidant enzyme activity,cause activation of anaerobic glycolysis in the myocardium. This metabolicheart impairment causes hemodynamic instability in postresuscitation period. 25mg/kg of carnosine injected during resuscitation decreased functional-metabolicheart impairments and hemodynamic disarrangement as well as earlypostresuscitation lethality. The authors attribute positive carnosine effect toits significant antioxidant activity.

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72. Rusakov VV, Dolgikh VT andKorpacheva OV (1993). [The membrane-protective effect of carnosine in thepost-resuscitation period after acute lethal blood loss]. Vopr Med Khim. 39:26-8. Activation of serum enzymes in male rats was detected during thepostresuscitation period after 4-6-min clinical death as a result of membranedestruction. Increase in the rate of lipid peroxidation and impairments ofenergy metabolism in the myocardium were responsible for destruction ofcardiomyocyte biomembranes. Administration of carnosine (25 mg/kg body weight)simultaneously with compensation for blood loss obviated the membrane lipidbilayer destruction and contributed to the development of the optimalconditions for membrane-bound enzymes.

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73. Sdvigova AG, Panasenko OM,Luk'iashchenko VI, Sergienko VI and Lopukhin Iu M (1993). [Correction oflipoprotein lipid peroxidation in experimental atherosclerosis withpolyunsaturated fatty acids combined with antioxidants]. Vopr Med Khim. 39:30-3. Atherosclerotic lesion of the aorta and lipid peroxidation (LPO) in bloodand in lipoproteins produced in hepatocytes were studied in rabbits withexperimental atherosclerosis maintained on a diet enriched in polyunsaturatedfatty acids containing in corn oil (2 ml/kg daily during 30 days) andantioxidants alpha-tocopherol and carnosine (2.5 mg/kg and 50 mg/kg,respectively, daily during 30 days). This diet exhibited a hypocholesterolemiceffect accompanied by approximately a 10-fold decrease of the impaired aorticarea, as well as lowered content of 2-thiobarbituric acid-positive LPO productsoccurring in blood and, especially, in apoB lipoproteins. Theantioxidant-containing diet decreased distinctly the content of LPO productsboth in the liver tissue homogenate and lipoprotein fraction (d < 1.065g/cm3) produced by hepatocytes during 30-min perfusion of liver tissue. Thefindings suggest that the diet enriched in polyunsaturated fatty acids andantioxidants contributed to a decrease of LPO products content in the bloodserum and apoB lipoproteins as well as to the inhibition of lipoproteinoxidation during their synthesis in liver cells; the diet may be recommendedfor the prophylaxis and treatment of atherosclerosis.

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74. Julia P, Young HH, BuckbergGD, Kofsky ER and Bugyi HI (1991). Studies of myocardial protection in theimmature heart. IV. Improved tolerance of immature myocardium to hypoxia andischemia by intravenous metabolic support. J Thorac Cardiovasc Surg. 101:23-32. University of California, Los Angeles School of Medicine, Department ofSurgery. Thirteen immature puppies (2 to 4 kg) underwent 1 hour of acutehypoxia (oxygen tension 25 to 30 mm Hg), followed by 45 minutes of normothermicglobal ischemia on total vented bypass with normal blood reperfusion.Ventricular function was assessed by inscribing Starling function curves andmeasuring stroke work indices before hypoxia and after reperfusion. Sevenpuppies (control) received normal saline infusion at 4 ml/kg/hr. Six otherpuppies received a 4 ml/kg/hr intravenous infusion of glutamate/aspartate,glucose-insulin-potassium, mercaptopropionyl glycine, carnitine, and catalaseduring hypoxia and reperfusion. In control hearts, acute hypoxia depletedmyocardial glutamate and aspartate by 52% (p less than 0.05 versus prehypoxia)and 48% (p less than 0.05 versus prehypoxia) and caused severe hemodynamicdeterioration (55% decrease of stroke work index) (p less than 0.05 versusprehypoxia); three of seven (43%) required premature institution of bypass.Postischemic left ventricular function recovered to only 40% of control levels(p less than 0.05 versus prehypoxia). In contrast, intravenous metabolicinfusions maintained tissue glutamate (p less than 0.05 versus control group)and aspartate (p less than 0.05 versus control group) in treated hearts duringhypoxia and allowed cardiac index to rise 20% (p less than 0.05 versusprehypoxia); all treated hearts tolerated 1 hour of hypoxia, and stroke workrecovered 70% (p less than 0.05 versus control group) of stroke work indexafter subsequent ischemia. Impaired tolerance of immature hearts to acutehypoxia and subsequent ischemia is due to substrate depletion. This impairmentcan be reduced by intravenous metabolic support during hypoxia and reperfusionand leads to improved recovery of postischemic function.

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75. Stvolinsky SL and Dobrota D(2000). Anti-ischemic activity of carnosine. Biochemistry (Mosc). 65: 849-55.Laboratory of Clinical Neurochemistry, Institute of Neurology, Russian Academyof Medical Sciences, Moscow, 123367 Russia. sls@bio.inevro.msk.ru. This reviewsummarizes the data on anti-ischemic activity of carnosine. The pronouncedanti-ischemic effects of carnosine in the brain and heart are due to thecombination of antioxidant and membrane-protecting activity, proton bufferingcapacity, formation of complexes with transition metals, and regulation ofmacrophage function. In experimental cerebral ischemia, carnosine decreasesmortality and is beneficial for neurological conditions of the animals. In cardiacischemia, carnosine protects cardiomyocytes from damage and improvescontractility of the heart. The data indicate that carnosine can be used as ananti-ischemic drug.

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76. Lee JW, Miyawaki H, Bobst EV,Hester JD, Ashraf M and Bobst AM (1999). Improved functional recovery ofischemic rat hearts due to singlet oxygen scavengers histidine and carnosine. JMol Cell Cardiol. 31: 113-21. Department of Chemistry, University of Cincinnati,OH 45221, USA. There is increasing evidence that reactive oxygen species (ROS)contribute to post-ischemic reperfusion injury, but determination of thespecific ROS involved has proven elusive. In the present study electronparamagnetic resonance (EPR) spectroscopy was used in vitro to measure therelative quenching of singlet oxygen (1O2) by histidine and carnosine(beta-alanyl-L-histidine) utilizing the hindered secondary amine2,2,6,6-tetramethyl-4-piperidone HCl (4-oxo-TEMP). The relative effect ofhistidine and carnosine on functional recovery of isolated perfused rat heartswas also studied. Functional recovery was measured by left ventriculardeveloped pressure (LVDP), first derivative of left ventricular pressure(dP/dt), heart rate (HR) and coronary flow (CF). EPR measurements andStern-Volmer plots showed that 400 microM carnosine quenched 1O2 twice aseffectively as equimolar histidine in vitro. Moreover, 10 mM histidine improvedfunctional recovery of isolated rat hearts significantly more than 1 mMhistidine. Furthermore, 1 mM carnosine improved functional recoverysignificantly more than equimolar histidine and as effectively as 10 mMhistidine. Experiments with 1 mM mannitol, a known hydroxyl radical scavenger,did not show an improvement in functional recovery relative to control hearts,thereby decreasing the likelihood that hydroxyl radicals are the major damagingspecies. On the other hand, the correlation between improved functionalrecovery of isolated rat hearts with histidine and carnosine and their relative1O2 quenching effectiveness in vitro provides indirect evidence for 1O2 as ROSparticipating in reperfusion injury.

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77. Yoshikawa T, Naito Y andKondo M (1993). Antioxidant therapy in digestive diseases. J Nutr Sci Vitaminol(Tokyo). 39 Suppl: S35-41. First Department of Medicine, Kyoto PrefecturalUniversity of Medicine, Japan. This paper reviewed the recent advance in theantioxidant therapy for digestive diseases. Many reports have supported thatlipid peroxidation mediated by oxygen radicals is implicated in thepathogenesis of gastric mucosal injury, intestinal damage, acute pancreatitis,and liver injury, and several kinds of antioxidant, which are divided into thepreventive antioxidant and chain-breaking antioxidant, are effective in thetreatment of these diseases. A new therapeutic approach using synthesizedantioxidants, such as zinc-carnosine chelate compound and ebselen, has beenalso proposed in these fields.

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78. Naumova OV, Goncharenko ENand Deev LI (1992). [The effect of carnosine on the liver enzyme system in theirradiated body]. Biokhimiia. 57: 1373-7. The effect of carnosine onpost-radioactive changes in lipid peroxidation (LPO) products in blood serumand cytochrome P-450 content in liver microsomes has been studied. Per osadministration of carnosine 24 hours prior to irradiation in a minimal lethaldose (7 Gr) markedly decreases the post-radioactive accumulation of LPOproducts in rat blood serum one hour after irradiation and fully restores thepost-radioactive decrease in the cytochrome P-450 content in rat livermicrosomes on day 5 after irradiation. Besides, the ability of carnosine toprevent the post-radioactive decline in the activity of UDP-glucuronyltransferase. Another key enzyme of the liver detoxifying system, has beendemonstrated. The data obtained testify to the ability of carnosine to provideeffective protection against post-radioactive intensification of LPO inirradiated organisms.

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79. Chan WK, Decker EA, Chow CKand Boissonneault GA (1994). Effect of dietary carnosine on plasma and tissueantioxidant concentrations and on lipid oxidation in rat skeletal muscle.Lipids. 29: 461-6. Department of Animal Sciences, University of Massachusetts,Amherst 01003. The effect of dietary carnosine supplementation on plasma andtissue carnosine and alpha-tocopherol concentrations and on the formation ofthiobarbituric acid reactive substances (TBARS) in rat skeletal musclehomogenates was evaluated. Plasma, heart, liver and hind leg muscle was obtainedfrom rats fed basal semipurified diets or basal diets containing carnosine(0.0875%), alpha-tocopheryl acetate (50 ppm), or carnosine (0.0875%) plusalpha-tocopheryl acetate (50 ppm). Dietary carnosine supplementation did notincrease carnosine concentrations in heart, liver and skeletal muscle. Dietarysupplementation with both carnosine and alpha-tocopherol increased carnosineconcentrations in liver 1.56, 1.51- and 1.51-fold as compared with dietslacking carnosine, alpha-tocopherol or both carnosine and alpha-tocopherol,respectively. Dietary supplementation with both carnosine and alpha-tocopherolalso increased alpha-tocopherol concentrations in heart and liver 1-38-fold and1.68-fold, respectively, as compared to supplementation with alpha-tocopherolalone. Dietary supplementation with carnosine, alpha-tocopherol or bothcarnosine and alpha-tocopherol was effective in decreasing the formation ofTBARS in rat skeletal muscle homogenate, with dietary alpha-tocopherol andalpha-tocopherol plus carnosine being more effective than dietary carnosinealone. The data suggest that dietary supplementation with carnosine andalpha-tocopherol modulates some tissue carnosine and alpha-tocopherolconcentrations and the formation of TBARS in rat skeletal muscle homogenates.

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80. Chan KM and Decker EA (1994).Endogenous skeletal muscle antioxidants. Crit Rev Food Sci Nutr. 34: 403-26.Chenoweth Laboratory, Department of Food Science, University of Massachusetts,Amherst, MA. Skeletal muscle is susceptible to oxidative deterioration due to acombination of lipid oxidation catalysts and membrane lipid systems that arehigh in unsaturated fatty acids. To prevent or delay oxidation reactions,several endogenous antioxidant systems are found in muscle tissue. These includealpha-tocopherol, histidine-containing dipeptides, and antioxidant enzymes suchas glutathione peroxidase, superoxide dismutase, and catalase. The contributionof alpha-tocopherol to the oxidative stability of skeletal muscle is largelyinfluenced by diet. Dietary supplementation of tocopherol has been shown toincrease muscle alpha-tocopherol concentrations and inhibit both lipidoxidation and color deterioration. Dietary selenium supplementation has alsobeen shown to increase the oxidative stability of muscle presumably byincreasing the activity of glutathione peroxidase. The oxidative stability ofskeletal muscle is also influenced by the histidine-containing dipeptides,carnosine and anserine. Whereas carnosine and anserine are affected by diet lessthan alpha-tocopherol and glutathione peroxidase, their concentrations varywidely with species and muscle type. In pigs, beef, and turkey muscle,carnosine concentrations are greater than anserine, while the opposite is truein rabbit, salmon, and chicken muscle. Anserine and carnosine are found ingreater concentrations in muscle high in white fibers, with chicken whitemuscle containing over fivefold more anserine and carnosine than red muscle.Anserine and carnosine are thought to inhibit lipid oxidation by a combinationof free radical scavenging and metal chelation.

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81. Quinn PJ, Boldyrev AA andFormazuyk VE (1992). Carnosine: its properties, functions and potentialtherapeutic applications. Mol Aspects Med. 13: 379-444. BiochemistryDepartment, King's College London, U.K. Carnosine and related dipeptides suchas anserine are naturally-occurring histidine-containing compounds. They arefound in several tissues most notably in muscle where they represent anappreciable fraction of the total water-soluble nitrogen-containing compounds.The biological role of these dipeptides are conjectural but they are believedto act as cytosolic buffering agents. Numerous studies have demonstrated, bothat the tissue and organelle level, that they possess strong and specificantioxidant properties. Carnosine and related dipeptides have been shown toprevent peroxidation of model membrane systems leading to the suggestion thatthey represent water-soluble counterparts to lipid-soluble antioxidants such asalpha-tocopherol in protecting cell membranes from oxidative damage. Otherroles ascribed to these dipeptides include actions as neurotransmitters,modulation of enzymic activities and chelation of heavy metals. Many claimshave been made in respect of therapeutic actions of carnosine andhistidine-containing dipeptides. These include antihypertensive effects,actions as immunomodulating agents, wound healing and antineoplastic effects.Many of these claims have not been convincingly documented nor subject torigorous clinical evaluation. Nevertheless, there are examples where studieshave shown considerable promise. One is the treatment of senile cataract indogs and another is in acceleration of healing of surface wounds and burns tothe skin. It is clear from this review that many of the effects of thesehistidine-containing dipeptides, especially in regard to claims for theirtherapeutic effects, need to be subjected to critical experimental and clinicalexamination. Several applications do, however, show clear evidence of beinguseful therapeutic agents.

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82. Reeve VE, Bosnic M andRozinova E (1993). Carnosine (beta-alanylhistidine) protects from thesuppression of contact hypersensitivity by ultraviolet B (280-320 nm) radiationor by cis urocanic acid. Immunology. 78: 99-104. Department of VeterinaryPathology, University of Sydney, Australia. Carnosine is a naturally occurringhistidine-containing dipeptide in mammalian tissues for which a physiologicalrole has not been defined. It has antioxidant properties, but has also beenshown to be related metabolically to histidine and histamine, and to haveimmunopotentiating properties in vivo. It is shown here that carnosinepresented topically or in the diet, potentiated the contact hypersensitivityreaction in hairless mice. Carnosine also prevented the systemic suppression ofthis reaction following exposure of the dorsal skin to ultraviolet B (UVB)radiation. Furthermore, carnosine prevented the systemic suppression caused bya topically applied lotion containing cis urocanic acid, indicating that it mayact in competition with this UVB photoproduct which is believed to initiatemany of the suppressive effects of UVB radiation.

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83. Hintz HF (1994). Nutritionand equine performance. J Nutr. 124: 2723S-2729S. Cornell University, Ithaca,NY 14853-4801. Some aspects of energy, protein and vitamin E nutrition of theperformance horse are discussed. The amount, dietary source and time ofingestion of energy before exercise can influence performance. In 1989 theNational Research Council (NRC) increased their estimates of energy required byracehorses. Recent studies indicate that the increase was reasonable. Manyfactors, however, can influence energy requirements. Therefore, the bestmeasure would be body weight and composition of the horse. A proper balance ofsoluble carbohydrate, fiber, fat and protein is essential. Some guidelines arepresented. The amount and type energy source given before exercise caninfluence level of plasma glucose and free fatty acids during exercise, but theeffects of these changes in the concentration of metabolites remains to bedetermined. There is no evidence that increased dietary concentrations ofprotein are needed and, in fact, may impair performance. Supplemental histidine(to enhance carnosine levels) or carnitine appear to be of limited value forhorses fed conventional diets. Dietary concentrations of vitamin E less thanthe 80 IU/kg recommended by NRC seem to adequately protect againstexercise-induced peroxidation. The NRC value may be justified on the basis ofimmune response, but further studies are needed. Vitamin E has been shown to beinvolved with familial equine degenerative myeloencephalopathy and may beinvolved with equine motor neuron disease, a condition considered to be similarto amyotrophic lateral sclerosis in humans.

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84. Shohami E, Gati I,Beit-Yannai E, Trembovler V and Kohen R (1999). Closed head injury in the ratinduces whole body oxidative stress: overall reducing antioxidant profile. JNeurotrauma. 16: 365-76. Department of Pharmacology, Hebrew University ofJerusalem, Israel. esty@cc.huji.ac.il. Traumatic injury to the brain triggersthe accumulation of harmful mediators, including highly toxic reactive oxygenspecies (ROS). Endogenous defense mechanism against ROS is provided by lowmolecular weight antioxidants (LMWA), reflected in the reducing power of thetissue, which can be measured by cyclic voltammetry (CV). CV records biologicalpeak potential (type of scavenger), and anodic current intensity (scavenger concentration).The effect of closed head injury (CHI) on the reducing power of various organswas studied. Water and lipid soluble extracts were prepared from the brain,heart, lung, kidney, intestine, skin, and liver of control and traumatized rats(1 and 24 h after injury) and total LMWA was determined. Ascorbic acid, uricacid, alpha-tocopherol, carotene and ubiquinol-10 were also identified by HPLC.The dynamic changes in LMWA levels indicate that the whole body responds toCHI. For example, transient reduction in LMWA (p<0.01) in the heart, kidney,lung and liver at 1 h suggests their consumption, probably due to interactionwith locally produced ROS. However, in some tissues (e.g., skin) there was anincrease (p<0.01), arguing for recruitment of higher than normal levels ofLMWA to neutralize the ROS. alpha-Tocopherol levels in the brain, liver, lung,skin, and kidney were significantly reduced (p<0.01) even up to 24 h. Weconclude that although the injury was delivered over the left cerebral hemisphere,the whole body appeared to be under oxidative stress, within 24 h after braininjury.

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85. Hirsch JD, Grillo M andMargolis FL (1978). Ligand binding studies in the mouse olfactory bulb:identification and characterization of a L-[3H]carnosine binding site. BrainRes. 158: 407-22. Binding sites for the dipeptide L-carnosine(beta-alanyl-L-histidine) have been detected in membranes prepared from mouseolfactory bulbs. The binding of L-[3H]-carnosine was saturable, reversible andstereospecific and had a Kd of about 770 nM. The stereospecific binding ofL-carnosine represented about 30% of the total binding at pH 6.8, and decreasedmarkedly with increasing pH. Binding was stimulated by calcium, unaffected byzinc, magnesium or manganese and inhibited by sodium and potassium. Carnosinebinding was sensitive to trypsin and phospholipases A and C, but not toneuraminidase. Nystatin and filipin, which interact with membrane lipids, alsointerferred with binding. Some peptide analogues of carnosine were potent inhibitorsof binding, but a variety of drugs serving as potent inhibitors in otherbinding systems had no effect on carnosine binding. Carnosine binding to mouseolfactory bulb membranes was 15-fold higher than that seen in membranesprepared from cerebral hemispheres, 5-fold higher than that seen in membranesprepared from cerebral hemispheres, 5-fold higher than in cerebellum membranesand 3-fold higher than in membranes from spinal medulla and the olfactorytubercle-lateral olfactory tract area. Binding sites for 6 other radiolabeledreceptor ligands were also detected in bulb membranes. Peripheraldeafferentation of the olfactory bulbs by intranasal irrigation with ZnSO4 ledto a loss greater than 90% of the L-[3H]carnosine binding in 4--5 days withmuch smaller losses in binding of the other 6 ligands over a 180-dayobservation period. This initial loss of carnosine binding after denervationwas due to a loss of binding site stereo-specificity followed by a loss ofbinding sites. The characteristics of the carnosine binding site in olfactorybulb fulfil 6 of the 7 criteria considered relevant for a functional receptor.

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86. De Marchis S, Modena C,Peretto P, Giffard C and Fasolo A (2000). Carnosine-like immunoreactivity inthe central nervous system of rats during postnatal development. J Comp Neurol.426: 378-90. Dipartimento di Biologia Animale e dell'Uomo, 10123 Torino, Italy.In the nervous system of adult rodents, the aminoacylhistidine dipeptides(carnosine and/or homocarnosine) have been shown to be expressed in three mainpopulations of cells: the mature olfactory receptor neurons, a subset of glialcells, and the neuroblasts of the rostral migratory stream. The current studyanalyzed the distribution of these dipeptides during postnatal development withinthe rat brain and spinal cord focusing on their pattern of appearance in theglial cells. Double staining methods using antibodies against carnosine andsome markers specific for immature (vimentin) and mature (glial fibrillaryacidic protein and Rip) glial cell types were used. Glial immunostaining forthe aminoacylhistidine dipeptides appears starting from postnatal day 6 andreaches the final distribution in 3-week-old animals. The occurrence ofcarnosine-like immunoreactivity in astrocytes lags behind that inoligodendrocytes suggesting that, as previously demonstrated by in vitrostudies, oligodendrocytes are also able to synthesize carnosine and/orhomocarnosine in vivo. Furthermore, the spatiotemporal patterns observedsupport the hypothesis that the production of these dipeptides coincides withthe final stages of glia differentiation. In addition, a strong carnosine-likeimmunoreactivity is transiently seen in a small population of cells localizedin the hypothalamus and in the subfornical organ from birth to postnatal day21. In these cells, carnosine-like immunoreactivity was not colocalized withany of the glial specific markers used. Moreover, no evidence forcolocalization of carnosine and gonadotropin-releasing hormone (GnRH) has beenobserved.

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87. Horning MS, Blakemore LJ andTrombley PQ (2000). Endogenous mechanisms of neuroprotection: role of zinc,copper, and carnosine. Brain Res. 852: 56-61. Biomedical Research Facility,Department of Biological Science, Florida State University, Tallahassee32306-4340, USA. horning@neuro.fsu.edu. Zinc and copper are endogenoustransition metals that can be synaptically released during neuronal activity.Synaptically released zinc and copper probably function to modulate neuronalexcitability under normal conditions. However, zinc and copper also can beneurotoxic, and it has been proposed that they may contribute to theneuropathology associated with a variety of conditions, such as Alzheimer'sdisease, stroke, and seizures. Recently, we demonstrated that carnosine, adipeptide expressed in glial cells throughout the brain as well as in neuronalpathways of the visual and olfactory systems, can modulate the effects of zincand copper on neuronal excitability. This result led us to hypothesize thatcarnosine may modulate the neurotoxic effects of zinc and copper as well. Ourresults demonstrate that carnosine can rescue neurons from zinc- andcopper-mediated neurotoxicity and suggest that one function of carnosine may beas an endogenous neuroprotective agent.

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88. Hoffmann AM, Bakardjiev A andBauer K (1996). Carnosine-synthesis in cultures of rat glial cells isrestricted to oligodendrocytes and carnosine uptake to astrocytes. NeurosciLett. 215: 29-32. Max-Planck-Institut fur experimentelle Endokrinologie,Hannover, Germany. Cultures of glial cells consisting predominantly ofoligodendrocytes and astrocytes were prepared to study whether the biosynthesisof carnosine (beta-Ala-His) and the cellular uptake of this dipeptide areprocesses which are associated with a specific cell type. Uptake of theradiolabeled precursor beta-alanine was observed in both cultures. Synthesis ofradiolabeled carnosine, however, was only observed in oligodendrocyte culturesprepared from rat brain and spinal cord. During oligodendrocyte cultivation weobserved a significant increase in the rate of carnosine synthesis whichcorrelates with the differentiation of these cells as revealed byimmunostaining with antibodies against oligodendrocyte markers. Carnosinesynthesis was not observed in astroglia cell cultures that were depleted ofresidual O2-A progenitor cells and oligodendrocytes by antibody mediatedcomplement cell killing. Contrary to the synthesis, carnosine was found to betaken up effectively only by astrocytes but not by oligodendrocytes.

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89. Baslow MH, Suckow RF, BergMJ, Marks N, Saito M and Bhakoo KK (2001). Differential expression ofcarnosine, homocarnosine and N-acetyl-L-histidine hydrolytic activities incultured rat macroglial cells. J Mol Neurosci. 17: 351-9. Nathan S. KlineInstitute for Psychiatric Research, Center for Neurochemistry, Orangeburg, NY10962, USA. Baslow@nki.rfmh.org. N-acetyl-L-histidine (NAH) andN-acetyl-L-aspartate (NAA) are representatives of two series of substances thatare synthesized by neurons and other cells in the vertebrate central nervoussystem (CNS). Histidine containing homologs of NAH are beta-alanyl-L-histidineor carnosine (Carn) and gamma-aminobutyrl-L-histidine or homocarnosine (Hcarn).A homolog of NAA is N-acetylaspartylglutamate (NAAG). These substances belongto a unique group of osmolytes in that they are synthesized in cells that maynot to be able to hydrolyze them, and are released in a regulated fashion to asecond compartment where they can be rapidly hydrolyzed. In this investigation,the catabolic activities for NAH, Carn, and Hcarn in cultured macroglial cellsand neurons have been measured, and the second compartment for NAH and Hcarnhas been identified only with astrocytes. In addition, oligodendrocytes can onlyhydrolyze Carn, although Carn can also be hydrolyzed by astrocytes. Thus,astrocytes express hydrolytic activity against all three substrates, butoligodendrocytes can only act on Carn. The cellular separation of thesehydrolytic enzyme activities, and the possible nature of the enzymes involvedare discussed.

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90. Bonfanti L, Peretto P, DeMarchis S and Fasolo A (1999). Carnosine-related dipeptides in the mammalianbrain. Prog Neurobiol. 59: 333-53. Dipartimento di Morfofisiologia Veterinaria,Universita degli Studi di Torino, Italy. Carnosine and structurally relateddipeptides are a group of histidine-containing molecules widely distributed invertebrate organisms and particularly abundant in muscle and nervous tissue.Although many theories have been proposed, the biological function(s) of thesecompounds in the nervous system remains enigmatic. The purpose of this articleis to review the distribution of carnosine-related dipeptides in the mammalianbrain, with particular reference to some cell populations wherein thesemolecules have been demonstrated to occur very recently. The high expression ofcarnosine in the mammalian olfactory receptor neurons led to infer that thisdipeptide could play a role as a neurotransmitter/modulator in olfaction. Thisprediction, which has not yet been fully demonstrated, does not explain thelocalization of carnosine-related dipeptides in other cell types, such as glialand ependymal cells. A recent demonstration of high carnosine-likeimmunoreactivity in the subependymal layer of rodents, an area of the forebrainwhich shares with the olfactory neuroepithelium the occurrence of continuousneurogenesis during adulthood, supports the hypothesis that carnosine-relateddipeptides could be implicated in some forms of structural plasticity. However,the particular distribution of these molecules in the subependymal layer, alongwith their expression in glial/ependymal cell populations, suggests that theyare not directly linked to cell migration or cell renewal. In the absence of aunified theory about the role of carnosine-related dipeptides in the nervoussystem, some common features shared by different cell populations of themammalian brain which contain these molecules are discussed.

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91. Bakardjiev A (1998).Carnosine and beta-alanine release is stimulated by glutamatergic receptors incultured rat oligodendrocytes. Glia. 24: 346-51. Max-Planck-Institut furexperimentelle Endokrinologie, Hannover, Germany. Oligodendrocytes obtainedfrom rat brain 0-2 A progenitor cells and differentiated in culture take upbeta-alanine and synthesize carnosine (beta-Ala-His). The present study wasdesigned to determine whether carnosine and beta-alanine are released from suchcultures in response to some stimuli. An evoked release of these substances wasnot observed when the cells were incubated with 1 mM glutamate or 0.3 mMkainate. Addition of 0.1 mM cyclothiazide (CTZ) to the corresponding stimuluswas accompanied by a distinct peak of release consisting of both carnosine andbeta-alanine. The efflux was blocked completely in the case of kainate and to80% in the case of glutamate when 50 microM 6,7-dinitroquinoxaline-2,3(1H,4H)-dion (DNQX) was added to the cells at the same time as the receptoragonist. An increase of the efflux was observed in the presence of Zn2+. Thiseffect was concentration-dependent. Total substitution of NaCl in the effluxmedium by LiCl caused only a partial reduction of the release. GABA or 55 mMKCl showed only negligible effect. A large release of carnosine andbeta-alanine was observed when oligodendrocyte cultures were treated with Ca2+ionophore A 23187. These results suggest that oligodendrocytes exhibit aglutamate receptor-mediated release of carnosine and beta-alanine. The releaseis dependent on elevated intracellular Ca2+ concentration.

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92. Sunderman FW, Jr. (2001).Nasal toxicity, carcinogenicity, and olfactory uptake of metals. Ann Clin LabSci. 31: 3-24. Department of Chemistry and Biochemistry, Middlebury College,Middlebury, Vermont, USA. 103040.3027@compuserve.com. Occupational exposures toinhalation of certain metal dusts or aerosols can cause loss of olfactoryacuity, atrophy of the nasal mucosa, mucosal ulcers, perforated nasal septum,or sinonasal cancer. Anosmia and hyposmia have been observed in workers exposedto Ni- or Cd-containing dusts in alkaline battery factories, nickel refineries,and cadmium industries. Ulcers of the nasal mucosa and perforated nasal septumhave been reported in workers exposed to Cr(VI) in chromate production andchrome plating, or to As(III) in arsenic smelters. Atrophy of the olfactoryepithelium has been observed in rodents following inhalation of NiSO4 oralphaNi3S2. Cancers of the nose and nasal sinuses have been reported in workersexposed to Ni compounds in nickel refining, cutlery factories, and alkalinebattery manufacture, or to Cr(VI) in chromate production and chrome plating. Inanimals, several metals (eg, Al, Cd, Co, Hg, Mn, Ni, Zn) have been shown topass via olfactory receptor neurons from the nasal lumen through the cribriformplate to the olfactory bulb. Some metals (eg, Mn, Ni, Zn) can cross synapses inthe olfactory bulb and migrate via secondary olfactory neurons to distantnuclei of the brain. After nasal instillation of a metal-containing solution,transport of the metal via olfactory axons can occur rapidly, within hours or afew days (eg, Mn), or slowly over days or weeks (eg, Ni). The olfactory bulbtends to accumulate certain metals (eg, Al, Bi, Cu, Mn, Zn) with greateravidity than other regions of the brain. The molecular mechanisms responsiblefor metal translocation in olfactory neurons and deposition in the olfactorybulb are unclear, but complexation by metal-binding molecules such as carnosine(beta-alanyl-L-histidine) may be involved.

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93. Petroff OA, Hyder F, MattsonRH and Rothman DL (1999). Topiramate increases brain GABA, homocarnosine, andpyrrolidinone in patients with epilepsy. Neurology. 52: 473-8. Department ofNeurology, Yale University, New Haven, CT 06520-8018, USA. OBJECTIVE: Tomeasure the effects of topiramate on brain gamma-aminobutyric acid (GABA) inpatients with epilepsy. BACKGROUND: Topiramate is a new antiepilepticmedication with multiple putative mechanisms of action. In a recentmeta-analysis of the newer antiepileptic drugs, topiramate was the most potent.Homocarnosine and pyrrolidinone are important metabolites of GABA with antiepilepticactions. METHODS: In vivo measurements of GABA, homocarnosine, andpyrrolidinone were made of a 14-cm3 volume in the occipital cortex using 1Hspectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cmsurface coil. Twelve patients (eight women) with refractory complex partialseizures were studied while using topiramate. Nine epilepsy-free, drug-freevolunteers served as control subjects. RESULTS: Topiramate increased mean brainGABA, homocarnosine, and pyrrolidinone concentrations in all patients. Inpaired measurements, brain GABA increased by 0.7 micromol/g (SD 0.3, n 7, 95%CI 0.4 to 1.0, p < 0.01). Homocarnosine increased by 0.5 micromol/g (SD 0.2,n 7, 95% CI 0.3 to 0.7, p < 0.001). Pyrrolidinone increased by 0.21 micromol/g(SD 0.06, n 7, 95% CI 0.16 to 0.27, p < 0.01). In two additional patients,GABA, homocarnosine, and pyrrolidinone increased after they were switched fromvigabatrin to topiramate. CONCLUSIONS: Topiramate increased brain GABA,homocarnosine, and pyrrolidinone to levels that could contribute to its potentantiepileptic action in patients with complex partial seizures.

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94. Petroff OA, Hyder F, RothmanDL and Mattson RH (2000). Effects of gabapentin on brain GABA, homocarnosine,and pyrrolidinone in epilepsy patients. Epilepsia. 41: 675-80. Department ofNeurology, Yale University, New Haven, Connecticut, USA. SUMMARY: PURPOSE:Gabapentin (GBP) was introduced as an antiepileptic drug (AED) and has beenused in the management of neuropathic pain. We reported that daily dosingincreased brain gamma-aminobutyric acid (GABA) in patients with epilepsy. Thisstudy was designed to determine how rapidly brain GABA and the GABAmetabolites, homocarnosine and pyrrolidinone, increase in response to the firstdose of GBP. METHODS: In vivo measurements of GABA, homocarnosine, andpyrrolidinone were made of a 14-cc volume in the occipital cortex by using a 1Hspectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cmsurface coil. Six patients (four women) were studied serially after the firstoral dose (1,200 mg) of GBP. Five patients (three women) taking a standarddaily dose (range, 1,200-2,000 mg) of GBP were rechallenged with a single highdose (2,400 mg). RESULTS: The first dose of GBP increased median brain GABA by1.3 mM (range, 0.4-1.8 mM) within 1 h. Homocarnosine and pyrrolidinone did notchange significantly by 5 h. Daily GBP therapy increased GABA (0.5 mM; 95% CI,0.2-0.9), homocarnosine (0.3 mM; 95% CI, 0.2-0.4), and pyrrolidinone (0.10 mM;95% CI, 0.06-0.14). Rechallenging patients taking GBP daily increased medianbrain GABA by 0.4 mM (range, 0.3-0.5) within 1 h. CONCLUSIONS: GBP promptlyelevates brain GABA and presumably offers partial protection against furtherseizures within hours of the first oral dose. Patients may expect to experiencethe anticonvulsant effects of increased homocarnosine and pyrrolidinone withdaily therapy.

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95. Petroff OA, Mattson RH, BeharKL, Hyder F and Rothman DL (1998). Vigabatrin increases human brainhomocarnosine and improves seizure control. Ann Neurol. 44: 948-52. Departmentof Neurology, Yale University, New Haven, CT 06520-8018, USA. Homocarnosine, adipeptide of gamma-aminobutyric acid (GABA) and histidine, is thought to be aninhibitory neuromodulator synthesized in subclasses of GABAergic neurons.Homocarnosine is present in human brain in greater amounts (0.4-1.0 micromol/g)than in other animals. The antiepileptic drug vigabatrin increases humancerebrospinal fluid homocarnosine linearly with daily dose. By using 1H nuclearmagnetic resonance spectroscopy, serial occipital lobe GABA and homocarnosineconcentrations were measured in 11 patients started on vigabatrin. Dailylow-dose (2 g) vigabatrin increased both homocarnosine and GABA. Larger dosesof vigabatrin (4 g) further increased homocarnosine but changed GABA levelsminimally. Seizure control improved with increasing homocarnosine and GABAconcentrations. Patients whose seizure control improved with the addition ofvigabatrin had higher mean homocarnosine, but the same mean GABAconcentrations, than those whose seizure control did not improve. Increasedhomocarnosine may contribute to improved seizure control.

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96. Petroff OA, Hyder F, CollinsT, Mattson RH and Rothman DL (1999). Acute effects of vigabatrin on brain GABAand homocarnosine in patients with complex partial seizures. Epilepsia. 40:958-64. Department of Neurology, Yale University, New Haven, Connecticut06520-8018, USA. PURPOSE: The acute, subacute, and chronic effects ofvigabatrin (VGB) were studied in patients with refractory complex partialseizures. VGB increases human brain gamma-aminobutyric acid (GABA) and therelated metabolites, homocarnosine and 2-pyrrolidinone. METHODS: In vivomeasurements of GABA and homocarnosine were made of a 14-cc volume in theoccipital cortex by using 1H spectroscopy with a 2.1-Tesla magnetic resonancespectrometer and an 8-cm surface coil. Six patients (three women) were studiedserially during the initiation and maintenance of VGB as adjunct therapy. RESULTS:The first, 3 g dose of VGB increased brain GABA by 2.0 micromol/g within 81 minof oral administration. After 2 h, median edited GABA remained essentially thesame for 2 days. The response to the second, 3-g dose of VGB given at 48 h wasconsiderably less than that to the first dose, with a median increase of 0.5micromol/g within 72 min. After 2-3 months, rechallenging patients taking 1.5-gVGB twice daily with 6 g increased GABA by 0.4 micromol/g within 87 min.Homocarnosine increased more gradually than GABA to above-normal levels after aweek of VGB therapy. CONCLUSIONS: VGB promptly elevates brain GABA andpresumably offers partial protection against further seizures within hours ofthe first oral dose. Once-a-day dosing is sufficient to increase GABA. Patientsmay be expected to experience the effects of increased homocarnosine within 1week.

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97. Goddard AW, Mason GF, AlmaiA, Rothman DL, Behar KL, Petroff OA, Charney DS and Krystal JH (2001).Reductions in occipital cortex GABA levels in panic disorder detected with1h-magnetic resonance spectroscopy. Arch Gen Psychiatry. 58: 556-61. YaleAnxiety Clinic, Yale Department of Psychiatry, 100 York St, Room 2J, New Haven,CT 06511, USA. andrew.goddard@yale.edu. BACKGROUND: There is preclinical evidenceand indirect clinical evidence implicating gamma-aminobutyric acid (GABA) inthe pathophysiology and treatment of human panic disorder. Specifically,deficits in GABA neuronal function have been associated with anxiogenesis,whereas enhancement of GABA function tends to be anxiolytic. Although reportedperipheral GABA levels (eg, in cerebrospinal fluid and plasma) have been withinreference limits in panic disorder, thus far there has been no directassessment of brain GABA levels in this disorder. The purpose of the presentwork was to determine whether cortical GABA levels are abnormally low inpatients with panic disorder. METHODS: Total occipital cortical GABA levels(GABA plus homocarnosine) were assessed in 14 unmedicated patients with panicdisorder who did not have major depression and 14 retrospectively age- andsex-matched control subjects using spatially localized (1)H-magnetic resonancespectroscopy. All patients met DSM-IV criteria for a principal currentdiagnosis of panic disorder with or without agoraphobia. RESULTS: Patients withpanic disorder had a 22% reduction in total occipital cortex GABA concentration(GABA plus homocarnosine) compared with controls. This finding was present in12 of 14 patient-control pairs and was not solely accounted for by medicationhistory. There were no significant correlations between occipital cortex GABAlevels and measures of illness or state anxiety. CONCLUSIONS: Panic disorder isassociated with reductions in total occipital cortex GABA levels. This abnormalitymight contribute to the pathophysiology of panic disorder.

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98. Pubill D, Verdaguer E, SuredaFX, Camins A, Pallas M, Camarasa J and Escubedo E (2002). Carnosine preventsmethamphetamine-induced gliosis but not dopamine terminal loss in rats. Eur JPharmacol. 448: 165-8. Unitat de Farmacological i Farmacognosia, Facultat deFarmacia, Universitat de Barcelona, Avgda. Diagonal 643, 08028 Barcelona,Spain. The neuroprotective effect of carnosine, an endogenous antioxidant, wasexamined against methamphetamine-induced neurotoxicity in rats. Carnosinepretreatment had no effect on dopamine terminal loss induced by methamphetamine(assessed by[3H]1-(2-[diphenylmethoxy]ethyl)-4-[3-phenylpropyl]piperazine([3H]GBR 12935)binding) but prevented microgliosis (increase in[3H]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxami de([3H]PK 11195) binding) in striatum. The 27-kDa heat-shock protein (HSP27)expression was used as indicator of astroglial stress. Methamphetaminetreatment induced the expression of HSP27 in striatum and hippocampus, whichwas inhibited by carnosine, indicating a protective effect. Carnosine had noeffect on methamphetamine-induced hyperthermia. Thus, carnosine prevents themicrogliosis in striatum (where we did not detect loss of serotonergicterminals by [3H]paroxetine binding) and the expression of HSP27 in all theareas, but fails to prevent methamphetamine-induced loss of dopamine reuptakesites. Therefore, carnosine inhibits only some of the consequences of methamphetamineneurotoxicity, where reactive oxygen species play an important role.

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99. Gallant S, Kukley M,Stvolinsky S, Bulygina E and Boldyrev A (2000). Effect of carnosine on ratsunder experimental brain ischemia. Tohoku J Exp Med. 191: 85-99. Zoetic NeurosciencesLtd., England, UK. The effect of dietary carnosine on the behavioral andbiochemical characteristics of rats under experimental ischemia was studied.Carnosine was shown to improve the animals orientation and learning in"Open Field" and "T-Maze" tests, and this effect wasaccompanied with an increase in glutamate binding to N-methyl-D-aspartate(NMDA) receptors in brain synaptosomes. Long-term brain ischemia induced byboth sides' occlusion of common carotid arteries resulted in 55% mortality of experimentalrats, and those who survived were characterized by partial suppression oforientation in T-maze. In the group of rats treated with carnosine, mortalityafter ischemic attack was decreased (from 55% to 17%) and most of the learningparameters were kept at the pre-ischemic level. Monoamine oxidase B (MAO B)activity in brain of the carnosine treated rats was not changed by ischemiasignificantly (compared to that of ischemic untreated rats) but NMDA binding tobrain synaptosomal membranes being increased by ischemic attack wassignificantly suppressed and reached the level characteristic of normal brain.The suggestion was made that carnosine possesses a dual effect on NMDAreceptors resulting in increase in their amount after long-term treatment butdecrease the capacity to bind NMDA after ischemic attack.

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