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Clinical Studies
References
Carnosine is a naturally occurring di-peptide found in skeletal muscle, heart, brain and other innervated tissues. Carnosine seems to be concentrated in actively contracting muscles. In people suffering from muscular dystrophies carnosine levels may be lower. The concentration of carnosine in muscles also appears to correlate with age. Older patients have lower muscle carnosine levels. Carnosine may play a role in the regulation of intracellular calcium and contractility in cardiac tissue.
Carnosine is of interest as an anti-aging product because of its effects on advance glycosylation end-products (AGEs). AGEs are abnormal, cross-linked and oxidized proteins that might play a role in the aging process. Carnosine may diminish the glycosylation of these proteins, preventing them from inducing cellular damage. Carnosine may be of benefit in complications of diabetes such as cataracts, neuropathy, and kidney failure, which arise from glycosylation.
Carnosine may play a role in preventing atherosclerosis, joint inflammation and cataract formation. Carnosine may also play a role in the prevention of Alzheimer's disease. Carnosine binds heavy metals and may provide some protection from zinc and copper mediated neurotoxicity. The ability of Carnosine to bind heavy metals may also be important in its ability to act as an antioxidant.
Carnosine protects against excitotoxicity and stroke. Many neurological disorders are caused by excitotoxicity. This brain cell damaging effect is often caused by excessive sensitivity to glutamate, the main excitatory neurotransmitter. Excitotoxicity triggers a cascade of events including membrane polarization, ending in cell death.
It is probable that excitotoxic complications determine the long-term effects of stroke. In Alzheimer's disease laboratory experiments show that amyloid-beta induces cultured neurons to undergo excitotoxic death.
Carnosine may be beneficial in aging processes such as neurological degeneration, cell aging, cross-linking of the eye lens, accumulation of damaged proteins, muscle atrophy, brain circulatory deficit, cross-linking of skin collagen, LDL cholesterol oxidation, formation of advanced glycation end products (AGEs) and DNA chromosome damage.
Published Clinical Studiesclin
1
Protective effects of carnosine, homocarnosine and anserine against peroxyl radical-mediated Cu,Zn-superoxide dismutase modification.
Kang JH, Kim KS, Choi SY, Kwon HY, Won MH, Kang TC.
Department of Genetic Engineering, Division of Natural Sciences, Chongju University, 360-764, South Korea. jhkang@chongju.ac.kr
Carnosine (beta-alanyl-L-histidine), homocarnosine (gamma-amino-butyryl-L-histidine) and anserine (beta-alanyl-1-methyl-L-histidine) have been proposed to act as anti-oxidants in vivo. The protective effects of carnosine and related compounds against the oxidative damage of human Cu,Zn-superoxide dismutase (SOD) by peroxyl radicals generated from 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) were studied. The oxidative damage to Cu,Zn-SOD by AAPH-derived radicals led to protein fragmentation, which is associated with the inactivation of enzyme. Carnosine, homocarnosine and anserine significantly inhibited the fragmentation and inactivation of Cu,Zn-SOD by AAPH. All three compounds also inhibited the release of copper ions from the enzyme and the formation of carbonyl compounds in AAPH-treated Cu,Zn-SOD. These compounds inhibited the fragmentation of other protein without copper ion. The results suggest that carnosine and related compounds act as the copper chelator and peroxyl radical scavenger to protect the protein fragmentation. Oxidation of amino acid residues in Cu,Zn-SOD induced by AAPH were significantly inhibited by carnosine and related compounds. It is proposed that carnosine and related dipeptides might be explored as potential therapeutic agents for pathologies that involve Cu,Zn-SOD modification mediated by peroxyl radicals.
PMID: 11985892 [PubMed - indexed for MEDLINE]
2
Antioxidant peptides with Angiotensin converting enzyme inhibitory activities and applications for Angiotensin converting enzyme purification.
Hou WC, Chen HJ, Lin YH.
Graduate Institute of Pharmacognosy, Taipei Medical University, Taiwan. wchou@tmu.edu.tw
Five commercial peptides, namely, reduced glutathione (GSH), oxidized glutathione (GSSG), carnosine, homocarnosine, and anserine, were used to test angiotensin converting enzyme inhibitory (ACEI) activities using N-[3-(2-furyl)acryloyl]-Phe-Gly-Gly (FAPGG) as a substrate. All of these peptides showed dose-dependent ACEI activities. Using 50% inhibition (IC(50)) of captopril as 0.00781 microM for the reference, the IC(50) values of GSH, carnosine, homocarnosine, and anserine were determined to be 32.4 microM, 5.216 mM, 6.147 mM, and 6.967 mM, respectively. GSH or carnosine showed mixed noncompetitive inhibition against ACE. When 0.0164 mM GSH or 0.4098 mM carnosine was added, the apparent inhibition constant (K(i)) was 49.7 microM or 3.899 mM, respectively. Commercial glutathione-Sepharose 4 fast flow, GSH-coupled CNBr-activated and GSH-coupled EAH-activated Sepharose gels were used for ACE purification. Commercial ACE could be adsorbed only by EAH-coupled GSH gels and eluted off the gels by increasing salt concentrations. These EAH-coupled GSH gels might be developed as affinity aids for ACE purification.
PMID: 12617609 [PubMed - in process]
AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?3
Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G.
Physiological Chemistry I, Biocenter, University of Wurzburg, Germany.
In Alzheimer's disease, age-related cellular changes such as compromised energy production and increased radical formation are worsened by the presence of AGEs as additional, AD specific stress factors. Intracellular AGEs (most likely derived from methylglyoxal) crosslink cytoskeletal proteins and render them insoluble. These aggregates inhibit cellular functions including transport processes and contribute to neuronal dysfunction and death. Extracellular AGEs, which accumulate in ageing tissue (but most prominently on long-lived protein deposits like the senile plaques) exert chronic oxidative stress on neurons. In addition, they activate glial cells to produce free radicals (superoxide and NO) and neurotoxic cytokines such as TNF-alpha. Drugs, which inhibit the formation of AGEs by specific chemical mechanisms (AGE-inhibitors), including aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate the development of (AGE-mediated) diabetic complications. Assuming that 'carbonyl stress' contributes significantly to the progression of Alzheimer's disease, AGE-inhibitors might also become interesting novel therapeutic drugs for treatment of AD.
Publication Types:
PMID: 11708614 [PubMed - indexed for MEDLINE]
In vitro and in vivo inhibition of muscle lipid and protein oxidation by carnosine.4
Nagasawa T, Yonekura T, Nishizawa N, Kitts DD.
Food and Health Science, Faculty of Agriculture, Iwate University, Morioka, Japan.
Carnosine, a beta-alanyl-L-histidine dipeptide with antioxidant properties is present at high concentrations in skeletal muscle tissue. In this study, we report on the antioxidant activity of carnosine on muscle lipid and protein stability from both in vitro and in vivo experiments. Carnosine inhibited lipid peroxidation and oxidative modification of protein in muscle tissue prepared from rat hind limb homogenates exposed to in vitro Fenton reactant (Fe2+, H2O2)-generated free radicals. The minimum effective concentrations of carnosine for lipid and protein oxidation were 2.5 and 1 mM, respectively. Histidine and beta-alanine, active components of carnosine, showed no individual effect towards inhibiting either lipid or protein oxidation. Skeletal muscle of rats fed a histidine supplemented diet for 13 days exhibited a marked increase in carnosine content with a concomitant reduction in muscle lipid peroxidation and protein carbonyl content in skeletal muscle caused by subjecting rats to a Fe-nitrilotriacetate administration treatment. This significant in vitro result confirms the in vivo antioxidant activity of carnosine for both lipid and protein constituents of muscle under physiological conditions.
PMID: 11716361 [PubMed - indexed for MEDLINE]
[In Process Citation]5
[Article in Russian]
[No authors listed]
Department of Neurochemistry, Institute of Neurology, Russian Academy of Medical Sciences, Volokolamskoc sh. 80, Moscow, 123367 Russia.
A comparative analysis of the antioxidant activity of a series of pharmacological compounds was performed in vitro using Fe2+ induced chemiluminescence of lipoproteins. With respect to the protective action against lipoprotein oxidation, the compounds studied can be arranged in the following order: trolox > carnosine > emoxypine > L-carnitine = mildronate. The results show good prospects for using the proposed chemiluminescent technique for evaluating the antioxidant activity of pharmaceuticals.
PMID: 14650218 [PubMed - in process]
6
Protective effect of carnosine on Cu,Zn-superoxide dismutase during impaired oxidative metabolism in the brain in vivo.
Stvolinskii SL, Fedorova TN, Yuneva MO, Boldyrev AA.
Institute of Neurology, Russian Academy of Medical Sciences, Moscow. sls@bio.inevro.msk.ru
Natural hydrophilic antioxidant carnosine protects cerebral cytosolic Cu,Zn-superoxide dismutase (SOD) under conditions of oxidative stress in various in vivo models: short-term hypobaric hypoxia in rats and accumulation of age-related changes in senescence-accelerated mice (SAMP). Administration of carnosine preventing Cu,Zn-SOD inactivation reduced mortality in rats and prolonged average life span in SAMP-mice.
PMID: 12802415 [PubMed - in process]
7
Possible role of L-carnosine in the regulation of blood glucose through controlling autonomic nerves.
Nagai K, Niijima A, Yamano T, Otani H, Okumra N, Tsuruoka N, Nakai M, Kiso Y.
Division of Protein Metabolism, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan. k_nagai@protein.osaka-u.ac.jp
Mammalian muscles synthesize L-carnosine, but its roles were unknown. Previously, we found in rats that the administration of a certain amount of L-carnosine elicited an inhibition of the hyperglycemia induced by the injection of 2-deoxy-D-glucose (2DG) into the lateral cerebral ventricle (LCV), and that intravenous injection of L-carnosine inhibited sympathetic nerves and facilitated the parasympathetic nerve. Moreover, the suppressive effect of L-carnosine on the hyperglycemia induced by 2DG was eliminated by thioperamide, a histaminergic H3 receptor. These findings suggested that L-carnosine might control the blood glucose level through regulating autonomic nerves via H3 receptor. To further clarify the function of L-carnosine, we examined its role in the control of the blood glucose. In this experiment, the following results were observed in rats: (i) A certain amount (0.01% or 0.001%) but not a larger amount (0.1%) of L-carnosine given as a diet suppressed the hyperglycemia induced by LCV-injection of 2DG (2DG-hyperglycemia); (ii) LCV-injection but not the injection into the intraperitoneal space (IP) of a certain amount of L-histidine suppressed the 2DG-hyperglycemia; (iii) treatments of diphenhydramine, an H1 antagonist, and alpha-fluoromethylhistidine, an inhibitor of histamine-synthesizing enzyme, reduced the 2DG-hyperglycemia; (iv) the plasma L-carnosine concentration and carnosinase activity showed daily changes; (v) the plasma L-carnosine concentration was significantly lower in the streptozotocin-diabetic rats; (vi) exercise by a running wheel tended to increase carnosine synthase activity in the gastrocnemius muscle and elevated the plasma L-carnosine concentration in the dark (active) period, and enhanced the plasma carnosinase activity in the light period; (vii) IP-injection of certain amount of L-carnosine stimulated the feeding response to IP-injection of 2DG. These findings suggest a possibility that L-carnosine released from muscles due to exercise functions to reduce the blood glucose level through the regulation of the autonomic nerves.
PMID: 14610252 [PubMed - indexed for MEDLINE]
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