Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders
José H. Cararo1, Emilio L. Streck2, Patricia F. Schuck1, Gustavo da C. Ferreira3,*()
1 Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduac?a?o em Cie?ncias da Sau?de, Universidade do Extremo Sul Catarinense, Criciu?ma, SC, Brazil 2 Laboratório de Bioenergética, Programa de Pós-Graduac?a?o em Cie?ncias da Sau?de, Universidade do Extremo Sul Catarinense, Criciu?ma, SC, Brazil 3 Laboratório de Bioenergética, Instituto de Bioqui?mica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Imidazole dipeptides (ID), such as carnosine (β-alanyl-L-histidine), are compounds widely distributed in excitable tissues of vertebrates. ID are also endowed of several biochemical properties in biological tissues, including antioxidant, bivalent metal ion chelating, proton buffering, and carbonyl scavenger activities. Furthermore, remarkable biological effects have been assigned to such compounds in age-related human disorders and in patients whose activity of serum carnosinase is deficient or undetectable. Nevertheless, the precise biological role of ID is still to be unraveled. In the present review we shall discuss some evidences from clinical and basic studies for the utilization of ID as a drug therapy for age-related human disorders.
Moya-Garcia AA, Medina MA, Sánchez-Jiménez F (2005). Mammalian histidine decarboxylase: from structure to function. Bioessays, 27:57-63.
Drozak J, Veiga-da-Cunha M, Vertommen D, Stroobant V, Van Schaftingen E (2010). Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). J Biol Chem, 285:9346-56.
Aldini G, Orioli M, Carini M, Maffei Facino R (2004). Profiling histidine-containing dipeptides in rat tissues by liquid chromatography/electrospray ionization tandem mass spectrometry. J Mass Spectrom, 39:1417-28.
Kish SJ, Perry TL, Hansen S (1979). Regional distribution of homocarnosine, homocarnosine-carnosine synthetase and homocarnosinase in human brain. J Neurochem, 32:1629-36.
Boldyrev AA, Severin SE (1990). The histidine-containing dipeptides, carnosine and anserine: distribution, properties and biological significance. Adv Enzyme Regul, 30:175-94.
Babizhayev MA, Deyev AI, Yegorov YE (2014). L-Carnosine modulates respiratory burst and reactive oxygen species production in neutrophil biochemistry and function: may oral dosage form of non-hydrolized dipeptide L-carnosine complement anti-infective anti-influenza flu treatment, prevention and self-care as an alternative to the conventional vaccination? Curr Clin Pharmacol, 9:93-115.
Jackson MC, Kucera CM, Lenney JF (1991). Purification and properties of human serum carnosinase. Clin Chim Acta, 196:193-205.
Quinn PJ, Boldyrev AA, Formazuyk VE (1992). Carnosine: its properties, functions and potential therapeutic applications. Mol Aspects Med, 13:379-444.
Hipkiss AR, Brownson C, Bertani MF, Ruiz E, Ferro A (2002). Reaction of carnosine with aged proteins: another protective process? Ann N Y Acad Sci, 959:285-94.
van Kuilenburg AB, Dobritzsch D, Meijer J, Meinsma R, Benoist JF, Assmann Bet al (2010). Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. Biochim Biophys Acta, 1802:639-48.
Gulewitsch W, Amiradžibi S (1900). Ueber das carnosin, eine neue organische base des fleischextractes. Ber Dtsch Chem Ges, 33:1902-3.
Babizhayev MA (2006). Biological activities of the natural imidazole-containing peptidomimetics N-acetylcarnosine, carcinine and L-carnosine in ophthalmic and skin care products. Life Sci, 78:2343-57.
Geissler S, Zwarg M, Knütter I, Markwardt F, Brandsch M (2010). The bioactive dipeptide anserine is transported by human proton-coupled peptide transporters. FEBS J, 277:790-5.
Bakardjiev A, Bauer K (1994). Transport of β-alanine and biosynthesis of carnosine by skeletal muscle cells in primary culture. Eur J Biochem, 225:617-23.
Hoffmann AM, Bakardjiev A, Bauer K (1996). Carnosine-synthesis in cultures of rat glial cells is restricted to oligodendrocytes and carnosine uptake to astrocytes. Neurosci Lett, 215:29-32.
Teufel M, Saudek V, Ledig JP, Bernhardt A, Boularand S, Carreau Aet al (2003). Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J Biol Chem, 278:6521-31.
Schoen P, Everts H, de Boer T, van Oeveren W (2003). Serum carnosinase activity in plasma and serum: validation of a method and values in cardiopulmonary bypass surgery. Clin Chem, 49:1930-2.
Otani H, Okumura A, Nagai K, Okumura N (2008). Colocalization of a carnosine-splitting enzyme, tissue carnosinase (CN2)/cytosolic non-specific dipeptidase 2 (CNDP2), with histidine decarboxylase in the tuberomammillary nucleus of the hypothalamus. Neurosci Lett, 445:166-9.
Manhiani PS, Northcutt JK, Han I, Bridges WC, Dawson PL (2013). Antioxidant activity of carnosine extracted from various poultry tissues. Poult Sci, 92:444-53.
Baran EJ (2000). Metal complexes of carnosine. Biochemistry (Mosc), 65:789-97.
Tanaka RA, Ramos FM, Almeida SM, Vizioli MR, Bóscolo FN (2005). Evaluation of radioprotective effect of carnosine (β-alanyl-L-histidine) on the wound healing in rats. J Appl Oral Sci, 13:253-8.
Abe H (2000). Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. Biochemistry (Mosc), 65:757-65.
Vistoli G, De Maddis D, Straniero V, Pedretti A, Pallavicini M, Valoti Eet al (2013). Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents. Eur J Med Chem, 66:153-60.
Aldini G, Orioli M, Rossoni G, Savi F, Braidotti P, Vistoli Get al (2011). The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J Cell Mol Med, 15:1339-54.
Ohsawa M, Mutoh J, Asato M, Yamamoto S, Ono H, Hisa Het al (2012). Carnosine has antinociceptive properties in the inflammation-induced nociceptive response in mice. Eur J Pharmacol, 682:56-61.
Li YF, He RR, Tsoi B, Li XD, Li WX, Abe Ket al (2012). Anti-stress effects of carnosine on restraint-evoked immunocompromise in mice through spleen lymphocyte number maintenance. PLoS One, 7:e33190.
Tomonaga S, Yamane H, Onitsuka E, Yamada S, Sato M, Takahata Yet al (2008). Carnosine-induced antidepressant-like activity in rats. Pharmacol Biochem Behav, 89:627-32.
Bellia F, Vecchio G, Cuzzocrea S, Calabrese V, Rizzarelli E (2011). Neuroprotective features of carnosine in oxidative driven diseases. Mol Aspects Med, 32:258-66.
Lin MT, Beal MF (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443:787-95.
Lenaz G, Bovina C, D'Aurelio M, Fato R, Formiggini G, Genova MLet al (2002). Role of mitochondria in oxidative stress and aging. Ann N Y Acad Sci, 959:199-213.
Petrosillo G, Matera M, Moro N, Ruggiero FM, Paradies G (2009). Mitochondrial complex I dysfunction in rat heart with aging: critical role of reactive oxygen species and cardiolipin. Free Radic Biol Med, 46:88-94.
Hunt ND, Hyun DH, Allard JS, Minor RK, Mattson MP, Ingram DKet al (2006). Bioenergetics of aging and calorie restriction. Ageing Res Rev, 5:125-43.
Rolo AP, Palmeira CM (2006). Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol, 212:167-78.
Bakala H, Ladouce R, Baraibar MA, Friguet B (2013). Differential expression and glycative damage affect specific mitochondrial proteins with aging in rat liver. Biochim Biophys Acta, 1832:2057-67.
Shigenaga MK, Hagen TM, Ames BN (1994). Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A, 91:10771-8.
Paradies G, Petrosillo G, Paradies V, Ruggiero FM (2010). Oxidative stress, mitochondrial bioenergetics, and cardiolipin in aging. Free Radic Biol Med, 48:1286-95.
Carter S, Caron A, Richard D, Picard F (2013). Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging, 8:829-44.
Kadish I, Thibault O, Blalock EM, Chen KC, Gant JC, Porter NMet al (2009). Hippocampal and cognitive aging across the lifespan: a bioenergetic shift precedes and increased cholesterol trafficking parallels memory impairment. J Neurosci, 29:1805-16.
Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013). Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal, 25:1939-48.
Aydín AF, Küskü-Kiraz Z, Doğru-Abbasoğlu S, Uysal M (2010). Effect of carnosine treatment on oxidative stress in serum, apoB-containing lipoproteins fraction and erythrocytes of aged rats. Pharmacol Rep, 62:733-9.
Batrukova MA, Rubtsov AM (1997). Histidine-containing dipeptides as endogenous regulators of the activity of sarcoplasmic reticulum Ca2+-release channels. Biochim Biophys Acta, 1324:142-50.
Rubtsov AM (2001). Molecular mechanisms of regulation of the activity of sarcoplasmic reticulum Ca2+-release channels (ryanodine receptors), muscle fatigue, and Severin's phenomenon. Biochemistry (Mosc), 66:1132-43.
Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M, Michaelis Jet al (1998). Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann N Y Acad Sci, 854:37-53.
Hipkiss AR (2010). Aging, Proteotoxicity, Mitochondria, Glycation, NAD and Carnosine: Possible Inter-Relationships and Resolution of the Oxygen Paradox. Front Aging Neurosci, 2:10.
Hipkiss AR (2000). Carnosine and protein carbonyl groups: a possible relationship. Biochemistry (Mosc), 65:771-8.
Pepper ED, Farrell MJ, Nord G, Finkel SE (2010). Antiglycation effects of carnosine and other compounds on the long-term survival of Escherichia coli. Appl Environ Microbiol, 76:7925-30.
Hipkiss AR (2009). On the enigma of carnosine's anti-ageing actions. Exp Gerontol, 44:237-42.
Carini M, Aldini G, Beretta G, Arlandini E, Facino RM (2003). Acrolein-sequestering ability of endogenous dipeptides: characterization of carnosine and homocarnosine/acrolein adducts by electrospray ionization tandem mass spectrometry. J Mass Spectrom, 38:996-1006.
Hipkiss AR (2011). Energy metabolism, proteotoxic stress and age-related dysfunction - protection by carnosine. Mol Aspects Med, 32:267-78.
Ikeda T, Kimura K, Hama T, Tamaki N (1980). Activation of rabbit muscle fructose 1,6-bisphosphatase by histidine and carnosine. J Biochem, 87:179-85.
Tejwani GA, Pedrosa FO, Pontremoli S, Horecker BL (1976). Dual role of Zn2+ as inhibitor and activator of fructose 1,6-bisphosphatase of rat liver. Proc Natl Acad Sci U S A, 73:2692-5.
Hipkiss AR, Cartwright SP, Bromley C, Gross SR, Bill RM (2013). Carnosine: can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential? Chem Cent J, 7:38.
Kantha SS, Wada S, Tanaka H, Takeuchi M, Watabe S, Ochi H (1996). Carnosine sustains the retention of cell morphology in continuous fibroblast culture subjected to nutritional insult. Biochem Biophys Res Commun, 223:278-82.
Shao L, Li QH, Tan Z (2004). L-Carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts. Biochem Biophys Res Commun, 324:931-6.
McFarland GA, Holliday R (1994). Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res, 212:167-75.
McFarland GA, Holliday R (1999). Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts. Exp Gerontol, 34:35-45.
Gallant S, Semyonova M, Yuneva M (2000). Carnosine as a potential anti-senescence drug. Biochemistry (Mosc), 65:866-8.
Stvolinsky S, Antipin M, Meguro K, Sato T, Abe H, Boldyrev A (2010). Effect of carnosine and its Trolox-modified derivatives on life span of Drosophila melanogaster. Rejuvenation Res, 13:453-7.
World Health Organization (2014). Priority eye diseases: Cataract. Available at: http://www.who.int/blindness/causes/priority/en/index1.html. Access in: January 18th 2014.
Toh T, Morton J, Coxon J, Elder MJ (2007). Medical treatment of cataract. Clin Experiment Ophthalmol, 35:664-71.
Crabbe MJ (1998). Cataract as a conformational disease - the Maillard reaction, α-crystallin and chemotherapy. Cell Mol Biol (Noisy-le-grand), 44:1047-50.
Dizhevskaya AK, Muranov KO, Boldyrev AA, Ostrovsky MA (2012). Natural dipeptides as mini-chaperones: molecular mechanism of inhibition of lens βL-crystallin aggregation. Curr Aging Sci, 5:236-41.
Babizhayev MA (2011). Mitochondria induce oxidative stress, generation of reactive oxygen species and redox state unbalance of the eye lens leading to human cataract formation: disruption of redox lens organization by phospholipid hydroperoxides as a common basis for cataract disease. Cell Biochem Funct, 29:183-206.
Babizhayev MA (1996). Failure to withstand oxidative stress induced by phospholipid hydroperoxides as a possible cause of the lens opacities in systemic diseases and ageing. Biochim Biophys Acta, 1315:87-99.
Babizhayev MA, Vishnyakova KS, Yegorov YE (2011). Telomere-dependent senescent phenotype of lens epithelial cells as a biological marker of aging and cataractogenesis: the role of oxidative stress intensity and specific mechanism of phospholipid hydroperoxide toxicity in lens and aqueous. Fundam Clin Pharmacol, 25:139-62.
Babizhayev MA (2004). Rejuvenation of visual functions in older adult drivers and drivers with cataract during a short-term administration of N-acetylcarnosine lubricant eye drops. Rejuvenation Res, 7:186-98.
Babizhayev MA, Deyev AI, Yermakova VN, Semiletov YA, Davydova NG, Kurysheva NIet al (2001). N-Acetylcarnosine, a natural histidine-containing dipeptide, as a potent ophthalmic drug in treatment of human cataracts. Peptides, 22:979-94.
Babizhayev MA, Deyev AI, Yermakova VN, Semiletov YA, Davydova NG, Doroshenko VSet al (2002). Efficacy of N-acetylcarnosine in the treatment of cataracts. Drugs R D, 3:87-103.
Babizhayev MA, Kasus-Jacobi A (2009). State of the art clinical efficacy and safety evaluation of N-acetylcarnosine dipeptide ophthalmic prodrug. Principles for the delivery, self-bioactivation, molecular targets and interaction with a highly evolved histidyl-hydrazide structure in the treatment and therapeutic management of a group of sight-threatening eye diseases. Curr Clin Pharmacol, 4:4-37.
Babizhayev MA, Guiotto A, Kasus-Jacobi A (2009). N-Acetylcarnosine and histidyl-hydrazide are potent agents for multitargeted ophthalmic therapy of senile cataracts and diabetic ocular complications. J Drug Target, 17:36-63.
Babizhayev MA, Burke L, Micans P, Richer SP (2009). N-Acetylcarnosine sustained drug delivery eye drops to control the signs of ageless vision: glare sensitivity, cataract amelioration and quality of vision currently available treatment for the challenging 50,000-patient population. Clin Interv Aging, 4:31-50.
Babizhayev MA, Micans P, Guiotto A, Kasus-Jacobi A (2009).N-Acetylcarnosine lubricant eyedrops possess all-in-one universal antioxidant protective effects of L-carnosine in aqueous and lipid membrane environments, aldehyde scavenging, and transglycation activities inherent to cataracts: a clinical study of the new vision-saving drug N-acetylcarnosine eyedrop therapy in a database population of over 50,500 patients. Am J Ther, 16:517-33.
Cloud A, Tandon A, Calhoun J, Cebulla CM (2012). Rapid formation and resolution of cataracts following orthopedic surgery for a patient with Charcot-Marie-Tooth disease. Arch Ophthalmol, 130:260-2.
Griffin WS (2006). Inflammation and neurodegenerative diseases. Am J Clin Nutr, 83:470S-474S.
Münch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Müller Ret al (1997). Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of β-amyloid peptide. Biochim Biophys Acta, 1360:17-29.
Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN (1998). Toxic effects of β-amyloid (25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and β-alanine. Neurosci Lett, 242:105-8.
Aloisi A, Barca A, Romano A, Guerrieri S, Storelli C, Rinaldi Ret al (2013). Anti-aggregating effect of the naturally occurring dipeptide carnosine on aβ1-42 fibril formation. PLoS One, 8:e68159.
Corona C, Frazzini V, Silvestri E, Lattanzio R, La Sorda R, Piantelli Met al (2011). Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One, 6:e17971.
Meier-Ruge W, Iwangoff P, Reichlmeier K (1984). Neurochemical enzyme changes in Alzheimer's and Pick's disease. Arch Gerontol Geriatr, 3:161-5.
Temperini C, Scozzafava A, Puccetti L, Supuran CT (2005). Carbonic anhydrase activators: X-ray crystal structure of the adduct of human isozyme II with L-histidine as a platform for the design of stronger activators. Bioorg Med Chem Lett, 15:5136-41.
Lovell MA, Xie C, Markesbery WR (2001). Acrolein is increased in Alzheimer's disease brain and is toxic to primary hippocampal cultures. Neurobiol Aging, 22:187-94.
Dei R, Takeda A, Niwa H, Li M, Nakagomi Y, Watanabe Met al (2002). Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease. Acta Neuropathol, 104:113-22.
Cheng J, Wang F, Yu DF, Wu PF, Chen JG (2011). The cytotoxic mechanism of malondialdehyde and protective effect of carnosine via protein cross-linking/mitochondrial dysfunction/reactive oxygen species/MAPK pathway in neurons. Eur J Pharmacol, 650:184-94.
Cornelli U (2010). Treatment of Alzheimer's disease with a cholinesterase inhibitor combined with antioxidants. Neurodegener Dis, 7:193-202.
Kim KS, Choi SY, Kwon HY, Won MH, Kang TC, Kang JH (2002). The ceruloplasmin and hydrogen peroxide system induces α-synuclein aggregation in vitro. Biochimie, 84:625-31.
Tsai SJ, Kuo WW, Liu WH, Yin MC (2010). Antioxidative and Anti-Inflammatory Protection from Carnosine in the Striatum of MPTP-Treated Mice. J Agric Food Chem, 58:11510-6.
DeCuypere M, Lu Y, Miller DD, LeDoux MS (2008). Regional distribution of tetrahydroisoquinoline derivatives in rodent, human, and Parkinson's disease brain. J Neurochem, 107:1398-413.
Kang JH (2010). Salsolinol, a catechol neurotoxin, induces modification of ferritin: Protection by histidine dipeptide. Environ Toxicol Pharmacol, 29:246-51.
Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Przuntek H, Kretschmer Aet al (1998). Elevated plasma levels of homocysteine in Parkinson's disease. Eur Neurol, 40(4):225-7.
Yasui K, Kowa H, Nakaso K, Takeshima T, Nakashima K (2000). Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD. Neurology, 55:437-40.
Boldyrev AA (2009). Molecular mechanisms of homocysteine toxicity. Biochemistry (Mosc), 74:589-98.
Boldyrev A, Bryushkova E, Mashkina A, Vladychenskaya E (2013). Why is homocysteine toxic for the nervous and immune systems? Curr Aging Sci, 6:29-36.
Boldyrev A, Fedorova T, Stepanova M, Dobrotvorskaya I, Kozlova E, Boldanova Net al (2008). Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson's disease: a pilot study. Rejuvenation Res, 11:821-7.
Vistoli G, Pedretti A, Cattaneo M, Aldini G, Testa B (2006). Homology modeling of human serum carnosinase, a potential medicinal target, and MD simulations of its allosteric activation by citrate. J Med Chem, 49:3269-77.
Janssen B, Hohenadel D, Brinkkoetter P, Peters V, Rind N, Fischer Cet al (2005). Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes, 54:2320-7.
Pearl PL, Jakobs C, Gibson KM (2007). Disorders of β- and γ-amino acids in free and peptide-linked forms. In: Scriver CR, Sly WS, Childs B, editors. The Online Metabolic & Molecular Bases of Inherited Disease. New York: McGraw-Hill.
Willi SM, Zhang Y, Hill JB, Phelan MC, Michaelis RC, Holden KR (1997). A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency. Pediatr Res, 41:210-3.
Perry TL, Hansen S, Tischler B, Bunting R, Berry K (1967). Carnosinemia. A new metabolic disorder associated with neurologic disease and mental defect. N Engl J Med, 277:1219-27.
van Heeswijk PJ, Trijbels JM, Schretlen ED, van Munster PJ, Monnens LA (1969). A patient with a deficiency of serum-carnosinase activity. Acta Paediatr Scand, 58:584-92.
Wisniewski K, Fleisher L, Rassin D, Lassmann H (1981). Neurological disease in a child with carnosinase deficiency. Neuropediatrics, 12:143-51.
Lunde HA, Gjessing LR, Sjaastad Ø (1986). Homocarnosinosis: influence of dietary restriction of histidine. Neurochem Res, 11:825-38.
Gjessing LR, Lunde HA, Mørkrid L, Lenney JF, Sjaastad Ø (1990). Inborn errors of carnosine and homocarnosine metabolism. J Neural Transm Suppl, 29:91-106.
Lenney JF, Peppers SC, Kucera CM, Sjaastad Ø (1983). Homocarnosinosis: lack of serum carnosinase is the defect probably responsible for elevated brain and CSF homocarnosine. Clin Chim Acta, 132:157-65.
Cohen M, Hartlage PL, Krawiecki N, Roesel RA, Carter AL, Hommes FA (1985). Serum carnosinase deficiency: a non-disabling phenotype? J Ment Defic Res, 29:383-9.
Sadiq S, Ghazala Z, Chowdhury A, Büsselberg D (2012). Metal toxicity at the synapse: presynaptic, postsynaptic, and long-term effects. J Toxicol, 2012:132671.
Lenney JF, George RP, Weiss AM, Kucera CM, Chan PW, Rinzler GS (1982). Human serum carnosinase: characterization, distinction from cellular carnosinase, and activation by cadmium. Clin Chim Acta, 123:221-31.
Everaert I, Mooyaart A, Baguet A, Zutinic A, Baelde H, Achten Eet al (2011). Vegetarianism, female gender and increasing age, but not CNDP1 genotype, are associated with reduced muscle carnosine levels in humans. Amino Acids, 40:1221-9.
Jansen EE, Gibson KM, Shigematsu Y, Jakobs C, Verhoeven NM (2006). A novel, quantitative assay for homocarnosine in cerebrospinal fluid using stable-isotope dilution liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci, 830:196-200.
Macarini JR, Maravai SG, Cararo JH, Dimer NW, Gonçalves CL, Kist LWet al (2014). Impairment of electron transfer chain induced by acute carnosine administration in skeletal muscle of young rats. Biomed Res Int, 2014:632986.
Boldyrev AA, Aldini G, Derave W (2013). Physiology and pathophysiology of carnosine. Physiol Rev, 93:1803-45.
Boldyrev AA, Stvolinsky SL, Fedorova TN, Suslina ZA (2010). Carnosine as a natural antioxidant and geroprotector: from molecular mechanisms to clinical trials. Rejuvenation Res, 13:156-8.