Carnosine: can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential?

Alan R Hipkiss, Stephanie P Cartwright, Clare Bromley, Stephane R Gross, Roslyn M Bill, Alan R Hipkiss, Stephanie P Cartwright, Clare Bromley, Stephane R Gross, Roslyn M Bill

Abstract

The dipeptide carnosine (β-alanyl-L-histidine) has contrasting but beneficial effects on cellular activity. It delays cellular senescence and rejuvenates cultured senescent mammalian cells. However, it also inhibits the growth of cultured tumour cells. Based on studies in several organisms, we speculate that carnosine exerts these apparently opposing actions by affecting energy metabolism and/or protein homeostasis (proteostasis). Specific effects on energy metabolism include the dipeptide's influence on cellular ATP concentrations. Carnosine's ability to reduce the formation of altered proteins (typically adducts of methylglyoxal) and enhance proteolysis of aberrant polypeptides is indicative of its influence on proteostasis. Furthermore these dual actions might provide a rationale for the use of carnosine in the treatment or prevention of diverse age-related conditions where energy metabolism or proteostasis are compromised. These include cancer, Alzheimer's disease, Parkinson's disease and the complications of type-2 diabetes (nephropathy, cataracts, stroke and pain), which might all benefit from knowledge of carnosine's mode of action on human cells.

Figures

Figure 1
Figure 1
(A) Structure of L-carnosine, the dipeptide β-alanyl-L-histidine; (B) structure of methylgloxal (2-oxopropanal).
Figure 2
Figure 2
An overview of glycolysis by which the conversion of glucose to pyruvate is coupled to the production of ATP for energy and NADH for biosynthesis. The entry of glycerol into the glycolytic pathway is also shown. The scheme indicates the hypothetical action of carnosine in the activation of fructose 1,6-bisphosphatase to create a futile, ATP-consuming, cycle which also inhibits glycolytic ATP generation.
Figure 3
Figure 3
Metabolic sources of methylglyoxal (MG) and the possible role of carnosine in scavenging MG and suppressing the formation of protein-AGEs. Protein-AGEs cause inflammation and ageing. MG-carnosine is excreted in urine.
Figure 4
Figure 4
The possible effects of carnosine on the formation and catabolism of abnormal proteins. MG, methyglyoxal; AGE, advanced glycation end-product; Hsp70, heat shock protein 70 (shown as an example).

References

    1. McFarland GA, Holliday R. Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res. 1994;212:167–175. doi: 10.1006/excr.1994.1132.
    1. Holliday R, McFarland GA. Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine. Br J Cancer. 1996;73:966–971. doi: 10.1038/bjc.1996.189.
    1. Bauer K. Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain. Neurochem Res. 2005;30:1339–1345. doi: 10.1007/s11064-005-8806-z.
    1. Boldyrev AA. Carnosine: new concept for the function of an old molecule. Biochemistry (Mosc) 2012;77:313–326. doi: 10.1134/S0006297912040013.
    1. Dunnett M, Harris RC. High-performance liquid chromatographic determination of imidazole dipeptides, histidine, 1-methylhistidine and 3-methylhistidine in equine and camel muscle and individual muscle fibres. J Chromatogr B Biomed Sci Appl. 1997;688:47–55. doi: 10.1016/S0378-4347(97)88054-1.
    1. Boldyrev A, Bulygina E, Leinsoo T, Petrushanko I, Tsubone S, Abe H. Protection of neuronal cells against reactive oxygen species by carnosine and related compounds. Comp Biochem Physiol B Biochem Mol Biol. 2004;137:81–88. doi: 10.1016/j.cbpc.2003.10.008.
    1. Fontana M, Pinnen F, Lucente G, Pecci L. Prevention of peroxynitrite-dependent damage by carnosine and related sulphonamido pseudodipeptides. Cell Mol Life Sci. 2002;59:546–551. doi: 10.1007/s00018-002-8446-2.
    1. Aldini G, Granata P, Carini M. Detoxification of cytotoxic alpha, beta-unsaturated aldehydes by carnosine: characterization of conjugated adducts by electrospray ionization tandem mass spectrometry and detection by liquid chromatography/mass spectrometry in rat skeletal muscle. J Mass Spectrom. 2002;37:1219–1228. doi: 10.1002/jms.381.
    1. Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun. 1998;248:28–32. doi: 10.1006/bbrc.1998.8806.
    1. Hipkiss AR, Michaelis J, Syrris P. Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent. FEBS Lett. 1995;371:81–85. doi: 10.1016/0014-5793(95)00849-5.
    1. Vistoli G, Orioli M, Pedretti A, Regazzoni L, Canevotti R, Negrisoli G, Carini M, Aldini G. Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species. ChemMedChem. 2009;4:967–975. doi: 10.1002/cmdc.200800433.
    1. Trombley PQ, Horning MS, Blakemore LJ. Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Biochemistry (Mosc) 2000;65:807–816.
    1. Abe H. Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. Biochemistry (Mosc) 2000;65:757–765.
    1. Ikeda D, Wada S, Yoneda C, Abe H, Watabe S. Carnosine stimulates vimentin expression in cultured rat fibroblasts. Cell Struct Funct. 1999;24:79–87. doi: 10.1247/csf.24.79.
    1. Kulebyakin K, Karpova L, Lakonsteva E, Krasavin M, Boldyrev A. Carnosine protects neurons against oxidative stress and modulates the time profile of MAPK cascade signaling. Amino Acids. 2012;43:91–96. doi: 10.1007/s00726-011-1135-4.
    1. Son DO, Satsu H, Kiso Y, Totsuka M, Shimizu M. Inhibitory effect of carnosine on interleukin-8 production in intestinal epithelial cells through translational regulation. Cytokine. 2008;42:265–276. doi: 10.1016/j.cyto.2008.02.011.
    1. Hipkiss AR. Energy metabolism, proteotoxic stress and age-related dysfunction - protection by carnosine. Mol Aspects Med. 2011;32:267–278. doi: 10.1016/j.mam.2011.10.004.
    1. Dang CV. Links between metabolism and cancer. Genes Dev. 2012;26:877–890. doi: 10.1101/gad.189365.112.
    1. Granchi C, Minutolo F. Anticancer agents that counteract tumor glycolysis. ChemMedChem. 2012;7:1318–1350. doi: 10.1002/cmdc.201200176.
    1. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–270.
    1. Funes JM, Quintero M, Henderson S, Martinez D, Qureshi U, Westwood C, Clements MO, Bourboulia D, Pedley RB, Moncada S, Boshoff C. Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production. Proc Natl Acad Sci U S A. 2007;104:6223–6228. doi: 10.1073/pnas.0700690104.
    1. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E. Energy metabolism in tumor cells. FEBS J. 2007;274:1393–1418. doi: 10.1111/j.1742-4658.2007.05686.x.
    1. Ertel A, Tsirigos A, Whitaker-Menezes D, Birbe RC, Pavlides S, Martinez-Outschoorn UE, Pestell RG, Howell A, Sotgia F, Lisanti MP. Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. Cell Cycle. 2012;11:253–263. doi: 10.4161/cc.11.2.19006.
    1. Natter K, Kohlwein SD. Yeast and cancer cells - common principles in lipid metabolism. Biochim Biophys Acta. 2013;1831:314–326. doi: 10.1016/j.bbalip.2012.09.003.
    1. Renner C, Asperger A, Seyffarth A, Meixensberger J, Gebhardt R, Gaunitz F. Carnosine inhibits ATP production in cells from malignant glioma. Neurol Res. 2010;32:101–105.
    1. Renner C, Zemitzsch N, Fuchs B, Geiger KD, Hermes M, Hengstler J, Gebhardt R, Meixensberger J, Gaunitz F. Carnosine retards tumor growth in vivo in an NIH3T3-HER2/neu mouse model. Mol Cancer. 2010;9:2. doi: 10.1186/1476-4598-9-2.
    1. Cartwright SP, Bill RM, Hipkiss AR. L-Carnosine Affects the Growth of Saccharomyces cerevisiae in a Metabolism-Dependent Manner. PLoS One. 2012;7:e45006. doi: 10.1371/journal.pone.0045006.
    1. Ikeda T, Kimura K, Hama T, Tamaki N. Activation of rabbit muscle fructose 1,6-bisphosphatase by histidine and carnosine. J Biochem. 1980;87:179–185.
    1. Garfinkel L, Garfinkel D. Magnesium regulation of the glycolytic pathway and the enzymes involved. Magnesium. 1985;4:60–72.
    1. Wallace DC. A mitochondrial paradigm for degenerative diseases and ageing. Novartis Found Symp. 2001;235:247–263.
    1. Agathocleous M, Love NK, Randlett O, Harris JJ, Liu J, Murray AJ, Harris WA. Metabolic differentiation in the embryonic retina. Nat Cell Biol. 2012;14:859–864. doi: 10.1038/ncb2531.
    1. De Marchis S, Modena C, Peretto P, Migheli A, Margolis FL, Fasolo A. Carnosine-related dipeptides in neurons and glia. Biochemistry (Mosc) 2000;65:824–833.
    1. Pognetto MS, Panzanelli P, Fasolo A, Cantino D. Expression of carnosine-like immunoreactivity during retinal development in the clawed frog (Xenopus laevis) Brain Res Dev Brain Res. 1992;70:134–138. doi: 10.1016/0165-3806(92)90111-9.
    1. Baguet A, Everaert I, Achten E, Thomis M, Derave W. The influence of sex, age and heritability on human skeletal muscle carnosine content. Amino Acids. 2012;43:13–20. doi: 10.1007/s00726-011-1197-3.
    1. Grinio L, Stvolinsky SL. Carnosine and muscle pathologies. International Congress on Exercise and Disease; Ghent. 2011. p. 46.
    1. Derave W, Everaert I, Beeckman S, Baguet A. Muscle carnosine metabolism and beta-alanine supplementation in relation to exercise and training. Sports Med. 2010;40:247–263. doi: 10.2165/11530310-000000000-00000.
    1. Nekrasova OE, Mendez MG, Chernoivanenko IS, Tyurin-Kuzmin PA, Kuczmarski ER, Gelfand VI, Goldman RD, Minin AA. Vimentin intermediate filaments modulate the motility of mitochondria. Mol Biol Cell. 2011;22:2282–2289. doi: 10.1091/mbc.E10-09-0766.
    1. Zakharchenko MV, Temnov AV, Kondrashova MN. Effect of carnosine on self-organization of mitochondrial assemblies in rat liver homogenate. Biochemistry (Mosc) 2003;68:1002–1005. doi: 10.1023/A:1026064613289.
    1. Chondrogianni N, Gonos ES. Proteasome function determines cellular homeostasis and the rate of aging. Adv Exp Med Biol. 2010;694:38–46. doi: 10.1007/978-1-4419-7002-2_4.
    1. Lionaki E, Markaki M, Tavernarakis N. Autophagy and ageing: Insights from invertebrate model organisms. Ageing Res Rev. 2013;12:413–428. doi: 10.1016/j.arr.2012.05.001.
    1. Herbert AP, Riesen M, Bloxam L, Kosmidou E, Wareing BM, Johnson JR, Phelan MM, Pennington SR, Lian LY, Morgan A. NMR structure of Hsp12, a protein induced by and required for dietary restriction-induced lifespan extension in yeast. PLoS One. 2012;7:e41975. doi: 10.1371/journal.pone.0041975.
    1. Salway KD, Gallagher EJ, Page MM, Stuart JA. Higher levels of heat shock proteins in longer-lived mammals and birds. Mech Ageing Dev. 2011;132:287–297. doi: 10.1016/j.mad.2011.06.002.
    1. Hipkiss AR. On the mechanisms of ageing suppression by dietary restriction-is persistent glycolysis the problem? Mech Ageing Dev. 2006;127:8–15. doi: 10.1016/j.mad.2005.09.006.
    1. Uchiki T, Weikel KA, Jiao W, Shang F, Caceres A, Pawlak D, Handa JT, Brownlee M, Nagaraj R, Taylor A. Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics) Aging Cell. 2012;11:1–13. doi: 10.1111/j.1474-9726.2011.00752.x.
    1. Hipkiss AR. Accumulation of altered proteins and ageing: causes and effects. Exp Gerontol. 2006;41:464–473. doi: 10.1016/j.exger.2006.03.004.
    1. Desai KM, Chang T, Wang H, Banigesh A, Dhar A, Liu J, Untereiner A, Wu L. Oxidative stress and aging: is methylglyoxal the hidden enemy? Can J Physiol Pharmacol. 2010;88:273–284. doi: 10.1139/Y10-001.
    1. Liu J, Wang R, Desai K, Wu L. Upregulation of aldolase B and overproduction of methylglyoxal in vascular tissues from rats with metabolic syndrome. Cardiovasc Res. 2011;92:494–503. doi: 10.1093/cvr/cvr239.
    1. Aldini G, Orioli M, Rossoni G, Savi F, Braidotti P, Vistoli G, Yeum KJ, Negrisoli G, Carini M. The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J Cell Mol Med. 2011;15:1339–1354. doi: 10.1111/j.1582-4934.2010.01101.x.
    1. Ohkawara T, Nishihira J, Nagashima R, Takeda H, Asaka M. Polaprezinc protects human colon cells from oxidative injury induced by hydrogen peroxide: relevant to cytoprotective heat shock proteins. World J Gastroenterol. 2006;12:6178–6181.
    1. Mikami K, Otaka M, Watanabe D, Goto T, Endoh A, Miura K, Ohshima S, Yoneyama K, Sato M, Shibuya T. Zinc L-carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72. J Gastroenterol Hepatol. 2006;21:1669–1674. doi: 10.1111/j.1440-1746.2006.04328.x.
    1. Bonner AB, Swann ME, Marway JS, Heap LC, Preedy VR. Lysosomal and nonlysosomal protease activities of the brain in response to ethanol feeding. Alcohol. 1995;12:505–509. doi: 10.1016/0741-8329(95)00035-6.
    1. Hipkiss AR, Brownson C, Bertani MF, Ruiz E, Ferro A. Reaction of carnosine with aged proteins: another protective process? Ann N Y Acad Sci. 2002;959:285–294.
    1. Dehvari N, Mahmud T, Persson J, Bengtsson T, Graff C, Winblad B, Ronnback A, Behbahani H. Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor. Neurochem Int. 2012;60:533–542. doi: 10.1016/j.neuint.2012.02.012.
    1. Pilecka I, Sadowski L, Kalaidzidis Y, Miaczynska M. Recruitment of APPL1 to ubiquitin-rich aggresomes in response to proteasomal impairment. Exp Cell Res. 2011;317:1093–1107. doi: 10.1016/j.yexcr.2011.02.002.
    1. Shimizu K, Kiuchi Y, Ando K, Hayakawa M, Kikugawa K. Coordination of oxidized protein hydrolase and the proteasome in the clearance of cytotoxic denatured proteins. Biochem Biophys Res Commun. 2004;324:140–146. doi: 10.1016/j.bbrc.2004.08.231.
    1. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. 2009;11:747–752. doi: 10.1038/ncb1881.
    1. Rodriguez-Rodriguez P, Fernandez E, Almeida A, Bolanos JP. Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death Differ. 2012;19:1582–1589. doi: 10.1038/cdd.2012.33.
    1. Almeida A, Bolanos JP, Moncada S. E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation. Proc Natl Acad Sci U S A. 2010;107:738–741. doi: 10.1073/pnas.0913668107.
    1. Hipkiss AR. Carnosine and its possible roles in nutrition and health. Adv Food Nutr Res. 2009;57:87–154.
    1. Maher PA, Schubert DR. Metabolic links between diabetes and Alzheimer's disease. Expert Rev Neurother. 2009;9:617–630. doi: 10.1586/ern.09.18.
    1. Mai A. Revelations into resveratrol's mechanism. Nat Med. 2012;18:500–501.
    1. Babizhayev MA, Seguin MC, Gueyne J, Evstigneeva RP, Ageyeva EA, Zheltukhina GA. L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities. Biochem J. 1994;304(Pt 2):509–516.
    1. Baran EJ. Metal complexes of carnosine. Biochemistry (Mosc) 2000;65:789–797.
    1. Kohen R, Yamamoto Y, Cundy KC, Ames BN. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci U S A. 1988;85:3175–3179. doi: 10.1073/pnas.85.9.3175.
    1. Chengappa KN, Turkin SR, DeSanti S, Bowie CR, Brar JS, Schlicht PJ, Murphy SL, Hetrick ML, Bilder R, Fleet D. A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia. Schizophr Res. 2012;142:145–152. doi: 10.1016/j.schres.2012.10.001.
    1. Boldyrev AA, Gallant SC, Sukhich GT. Carnosine, the protective, anti-aging peptide. Biosci Rep. 1999;19:581–587. doi: 10.1023/A:1020271013277.
    1. Gaunitz F, Hipkiss AR. Carnosine and cancer: a perspective. Amino Acids. 2012;43:135–142. doi: 10.1007/s00726-012-1271-5.
    1. Scheper GC, Proud CG. Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation? Eur J Biochem. 2002;269:5350–5359. doi: 10.1046/j.1432-1033.2002.03291.x.
    1. Yellen P, Saqcena M, Salloum D, Feng J, Preda A, Xu L, Rodrik-Outmezguine V, Foster DA. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle. 2011;10:3948–3956. doi: 10.4161/cc.10.22.18124.
    1. Villa-Cuesta E, Boylan JM, Tatar M, Gruppuso PA. Resveratrol inhibits protein translation in hepatic cells. PLoS One. 2011;6:e29513. doi: 10.1371/journal.pone.0029513.
    1. Logsdon CD, Fuentes MK, Huang EH, Arumugam T. RAGE and RAGE ligands in cancer. Curr Mol Med. 2007;7:777–789. doi: 10.2174/156652407783220697.
    1. Abe R, Yamagishi S. AGE-RAGE system and carcinogenesis. Curr Pharm Des. 2008;14:940–945. doi: 10.2174/138161208784139765.
    1. Pietkiewicz J, Bronowicka-Szydelko A, Dzierzba K, Danielewicz R, Gamian A. Glycation of the muscle-specific enolase by reactive carbonyls: effect of temperature and the protection role of carnosine, pyridoxamine and phosphatidylserine. Protein J. 2011;30:149–158. doi: 10.1007/s10930-011-9307-3.
    1. Alhamdani MS, Al-Kassir AH, Abbas FK, Jaleel NA, Al-Taee MF. Antiglycation and antioxidant effect of carnosine against glucose degradation products in peritoneal mesothelial cells. Nephron Clin Pract. 2007;107:c26–c34. doi: 10.1159/000106509.
    1. Alhamdani MS, Al-Azzawie HF, Abbas FK. Decreased formation of advanced glycation end-products in peritoneal fluid by carnosine and related peptides. Perit Dial Int. 2007;27:86–89.
    1. Bellia F, Vecchio G, Cuzzocrea S, Calabrese V, Rizzarelli E. Neuroprotective features of carnosine in oxidative driven diseases. Mol Aspects Med. 2011;32:258–266. doi: 10.1016/j.mam.2011.10.009.
    1. Hipkiss AR. Dietary restriction, glycolysis, hormesis and ageing. Biogerontology. 2007;8:221–224. doi: 10.1007/s10522-006-9034-x.
    1. Hipkiss AR. Could carnosine or related structures suppress Alzheimer's disease? J Alzheimers Dis. 2007;11:229–240.
    1. Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN. Toxic effects of beta-amyloid(25–35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Neurosci Lett. 1998;242:105–108. doi: 10.1016/S0304-3940(98)00058-5.
    1. Fu Q, Dai H, Hu W, Fan Y, Shen Y, Zhang W, Chen Z. Carnosine protects against Abeta42-induced neurotoxicity in differentiated rat PC12 cells. Cell Mol Neurobiol. 2008;28:307–316. doi: 10.1007/s10571-007-9235-0.
    1. Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham AM. Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta. 1997;1360:17–29. doi: 10.1016/S0925-4439(96)00062-2.
    1. Corona C, Frazzini V, Silvestri E, Lattanzio R, La Sorda R, Piantelli M, Canzoniero LM, Ciavardelli D, Rizzarelli E, Sensi SL. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One. 2011;6:e17971. doi: 10.1371/journal.pone.0017971.
    1. Scozzafava A, Supuran CT. Carbonic anhydrase activators: high affinity isozymes I, II, and IV activators, incorporating a beta-alanyl-histidine scaffold. J Med Chem. 2002;45:284–291. doi: 10.1021/jm010958k.
    1. Kida E, Palminiello S, Golabek AA, Walus M, Wierzba-Bobrowicz T, Rabe A, Albertini G, Wisniewski KE. Carbonic anhydrase II in the developing and adult human brain. J Neuropathol Exp Neurol. 2006;65:664–674. doi: 10.1097/01.jnen.0000225905.52002.3e.
    1. Fasseas MK, Tsikou D, Flemetakis E, Katinakis P. Molecular and biochemical analysis of the alpha class carbonic anhydrases in Caenorhabditis elegans. Mol Biol Rep. 2011;38:1777–1785. doi: 10.1007/s11033-010-0292-y.
    1. Boldyrev A, Fedorova T, Stepanova M, Dobrotvorskaya I, Kozlova E, Boldanova N, Bagyeva G, Ivanova-Smolenskaya I, Illarioshkin S. Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson's disease: a pilot study. Rejuvenation Res. 2008;11:821–827. doi: 10.1089/rej.2008.0716.
    1. Boldyrev AA, Stvolinsky SL, Fedorova TN, Suslina ZA. Carnosine as a natural antioxidant and geroprotector: from molecular mechanisms to clinical trials. Rejuvenation Res. 2010;13:156–158. doi: 10.1089/rej.2009.0923.
    1. Licker V, Cote M, Lobrinus JA, Rodrigo N, Kovari E, Hochstrasser DF, Turck N, Sanchez JC, Burkhard PR. Proteomic profiling of the substantia nigra demonstrates CNDP2 overexpression in Parkinson's disease. J Proteomics. 2012;75:4656–4667. doi: 10.1016/j.jprot.2012.02.032.
    1. Deng Y, Zhang Y, Li Y, Xiao S, Song D, Qing H, Li Q, Rajput AH. Occurrence and distribution of salsolinol-like compound, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ) in parkinsonian brains. J Neural Transm. 2012;119:435–441. doi: 10.1007/s00702-011-0724-4.
    1. Kang JH. Salsolinol, a catechol neurotoxin, induces modification of ferritin: Protection by histidine dipeptide. Environ Toxicol Pharmacol. 2010;29:246–251. doi: 10.1016/j.etap.2010.01.007.
    1. Hipkiss AR. Parkinson’s Disease and Type-2 Diabetes: Methylglyoxal may be a Common Causal Agent; Carnosine could be Protective. Mol Med Ther. 2012;1:2.
    1. Kumar PA, Kumar MS, Reddy GB. Effect of glycation on alpha-crystallin structure and chaperone-like function. Biochem J. 2007;408:251–258. doi: 10.1042/BJ20070989.
    1. Kim J, Sohn E, Kim CS, Kim JS. Renal podocyte apoptosis in Zucker diabetic fatty rats: involvement of methylglyoxal-induced oxidative DNA damage. J Comp Pathol. 2011;144:41–47. doi: 10.1016/j.jcpa.2010.04.008.
    1. Negre-Salvayre A, Salvayre R, Auge N, Pamplona R, Portero-Otin M. Hyperglycemia and glycation in diabetic complications. Antioxid Redox Signal. 2009;11:3071–3109. doi: 10.1089/ars.2009.2484.
    1. Aviles-Olmos I, Limousin P, Lees A, Foltynie T. Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain. 2013;136:374–384. doi: 10.1093/brain/aws009.
    1. Vincent A, Briggs L, Chatwin GF, Emery E, Tomlins R, Oswald M, Middleton CA, Evans GJ, Sweeney ST, Elliott CJ. Parkin-induced defects in neurophysiology and locomotion are generated by metabolic dysfunction and not oxidative stress. Hum Mol Genet. 2012;21:1760–1769. doi: 10.1093/hmg/ddr609.
    1. Wahlqvist ML, Lee MS, Hsu CC, Chuang SY, Lee JT, Tsai HN. Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord. 2012;18:753–758. doi: 10.1016/j.parkreldis.2012.03.010.
    1. Rabbani N, Thornalley PJ. Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids. 2012;42:1133–1142. doi: 10.1007/s00726-010-0783-0.
    1. Hipkiss AR. Would carnosine or a carnivorous diet help suppress aging and associated pathologies? Ann N Y Acad Sci. 2006;1067:369–374. doi: 10.1196/annals.1354.052.
    1. Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, Sauer SK, Eberhardt M, Schnolzer M, Lasitschka F. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med. 2012;18:926–933. doi: 10.1038/nm.2750.
    1. Eberhardt MJ, Filipovic MR, Leffler A, de la Roche J, Kistner K, Fischer MJ, Fleming T, Zimmermann K, Ivanovic-Burmazovic I, Nawroth PP. Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1): a possible mechanism of metabolic neuropathies. J Biol Chem. 2012;287:28291–28306. doi: 10.1074/jbc.M111.328674.
    1. Kamei J, Ohsawa M, Miyata S, Tanaka S. Preventive effect of L-carnosine on changes in the thermal nociceptive threshold in streptozotocin-induced diabetic mice. Eur J Pharmacol. 2008;600:83–86. doi: 10.1016/j.ejphar.2008.10.002.
    1. Ohsawa M, Mutoh J, Asato M, Yamamoto S, Ono H, Hisa H, Kamei J. Carnosine has antinociceptive properties in the inflammation-induced nociceptive response in mice. Eur J Pharmacol. 2012;682:56–61. doi: 10.1016/j.ejphar.2012.02.005.
    1. Everaert I, Taes Y, De Heer E, Baelde H, Zutinic A, Yard B, Sauerhofer S, Vanhee L, Delanghe J, Aldini G, Derave W. Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans. Am J Physiol Renal Physiol. 2012;302:F1537–F1544. doi: 10.1152/ajprenal.00084.2012.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever