Advertisement

Neurotoxicity Research

, Volume 34, Issue 1, pp 164–172 | Cite as

Glycotoxins: Dietary and Metabolic Origins; Possible Amelioration of Neurotoxicity by Carnosine, with Special Reference to Parkinson’s Disease

  • Alan R. Hipkiss
REVIEW
  • 220 Downloads

Abstract

There is a strong association between neurodegeneration and protein glycation; possible origins of neurotoxic glycated protein, also called glycotoxins, include (i) diet (i.e., proteins cooked at high temperatures), (ii) protein glycation in the gut, and (iii) intracellular reaction of proteins with deleterious aldehydes, especially methylglyoxal (MG). It is likely that excessive glycolysis provokes increased generation of dihydroxyacetone phosphate which decomposes into MG due to activity-induced deamidation of certain asparagine residues in the glycolytic enzyme triose-phosphate isomerase (TPI). It is suggested that, following hyperglycemia, erythrocytes (i) possibly participate in MG distribution throughout the body and (ii) could provide a source of glycated alpha-synuclein which also accumulates in PD brains as Lewy bodies. The dipeptide carnosine, recently shown to be present in erythrocytes, could help to protect against MG reactivity by scavenging the reactive bicarbonyl, especially if glyoxalase activity is insufficient, as often occurs during aging. By reacting with MG, carnosine may also prevent generation of the neurotoxin 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ), which accumulates in PD and diabetic brains. It is suggested that carnosine’s therapeutic potential could be explored via nasal administration in order to avoid the effects of serum carnosinase. The possibility that some glycated proteins (e.g., alpha-synuclein) could possess prion-like properties is also considered.

Keywords

Glycation Methylglyoxal Triose-phosphate isomerase Carnosine Erythrocytes Glycolysis Diet Prion Alpha-synuclein 

References

  1. Abate G, Marziano M, Rungratanawanich W, Memo M, Uberti D (2017) Nutrition and AGE-ing: focusing on Alzheimer’s disease. Oxidative Med Cell Longev 2017:7039816–7039810.  https://doi.org/10.1155/2017/7039816 Google Scholar
  2. Adolphe JL, Drew MD, Huang Q, Silver TI, Weber LP (2012) Postprandial impairment of flow-mediated dilation and elevated methylglyoxal after simple but not complex carbohydrate consumption in dogs. Nutr Res 32(4):278–284.  https://doi.org/10.1016/j.nutres.2012.03.002 PubMedGoogle Scholar
  3. Afshin-Majd S, Khalili M, Roghani M, Mehranmehr N, Baluchnejadmojarad T (2015) Carnosine exerts neuroprotective effect against 6-hydroxydopamine toxicity in hemiparkinsonian rat. Mol Neurobiol 51(3):1064–1070.  https://doi.org/10.1007/s12035-014-8771-0 PubMedGoogle Scholar
  4. Alhamdani MS, Al-Kassir AH, Abbas FK, Jaleel NA, Al-Taee MF (2007) Antiglycation and antioxidant effect of carnosine against glucose degradation products in peritoneal mesothelial cells. Nephron Clin Pract 107:26–34Google Scholar
  5. Allaman I, Bélanger M, Magistretti PJ (2015) Methylglyoxal, the dark side of glycolysis. Neurosci 9:23.  https://doi.org/10.3389/fnins.2015.00023 CrossRefGoogle Scholar
  6. Aloisi A, Barca A, Romano S, Guerrieri C, Storelli R, Rinaldi TV (2013) Anti-aggregating effect of the naturally occurring dipeptide carnosine on abeta1-42 fibril formation. PLoS One 8(7):e68159.  https://doi.org/10.1371/journal.pone.0068159 PubMedPubMedCentralGoogle Scholar
  7. Angoorani P, Ejtahed HS, Mirmiran P, Mirzaei S, Azizi F (2016) Dietary consumption of advanced glycation end products and risk of metabolic syndrome. Int J Food Sci Nutr 67(2):170–176.  https://doi.org/10.3109/09637486.2015.1137889 PubMedGoogle Scholar
  8. Ansurudeen I, Sunkari VG, Grünler J, Peters V, Schmitt CP, Catrina SB, Brismar K, Forsberg EA (2012) Carnosine enhances diabetic wound healing in the db/db mouse model of type 2 diabetes. Amino Acids 43(1):127–134.  https://doi.org/10.1007/s00726-012-1269-z PubMedGoogle Scholar
  9. Antikainen H, Driscoll M, Haspel G, Dobrowolski R (2017) TOR-mediated regulation of metabolism in aging. Aging Cell 16(6):1219–1233.  https://doi.org/10.1111/acel.12689 PubMedPubMedCentralGoogle Scholar
  10. Aruoma OI, Laughton MJ, Halliwell B (1989) Carnosine, homocarnosine and anserine: could they act as antioxidants in vivo? Biochem J 264(3):863–869.  https://doi.org/10.1042/bj2640863 PubMedPubMedCentralGoogle Scholar
  11. Attanasio F, Convertino M, Magno A, Caflisch A, Corazza A, Haridas H, Esposito G, Cataldo S, Pignataro B, Milardi D, Rizzarelli E (2013) Carnosine inhibits Aβ(42) aggregation by perturbing the H-bond network in and around the central hydrophobic cluster. Chembiochem 14(5):583–592.  https://doi.org/10.1002/cbic.201200704 PubMedGoogle Scholar
  12. Auburger G, Kurz A (2011) The role of glyoxalases for sugar stress and aging, with relevance for dyskinesia, anxiety, dementia and Parkinson’s disease. Aging (Albany NY) 3(1):5–9.  https://doi.org/10.18632/aging.100258 Google Scholar
  13. Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, Fitzgerald SD, Farooq MU, Naravelta B, Bhatt A, Majid A (2013) Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Stroke 44(1):205–212.  https://doi.org/10.1161/STROKEAHA.112.673954 PubMedGoogle Scholar
  14. Baek SH, Noh AR, Kim KA, Akram M, Shin YJ, Kim ES, Yu SW, Majid A, Bae ON (2014) Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke 45(8):2438–2443.  https://doi.org/10.1161/STROKEAHA.114.005183 PubMedPubMedCentralGoogle Scholar
  15. Bains Y, Gugliucci A (2017) Ilex paraguariensis and its main component chlorogenic acid inhibit fructose formation of advanced glycation endproducts with amino acids at conditions compatible with those in the digestive system. Fitoterapia 117:6–10.  https://doi.org/10.1016/j.fitote.2016.12.006 PubMedGoogle Scholar
  16. Bala KA, Doğan M, Mutluer T, Kaba S, Aslan O, Balahoroğlu R, Çokluk E, Üstyol L, Kocaman S (2016) Plasma amino acid profile in autism spectrum disorder (ASD). Plasma amino acid profile in autism spectrum disorder (ASD). Eur Rev Med Pharmacol 20:923–929Google Scholar
  17. Bao Y, Ding S, Cheng J, Liu Y, Wang B, Xu H, Shen Y, Lyu J (2016) Carnosine inhibits the proliferation of human cervical gland carcinoma cells through inhibiting both mitochondrial bioenergetics and glycolysis pathways and retarding cell cycle progression. Integr Cancer Ther 1:1534735416684551.  https://doi.org/10.1177/1534735416684551 CrossRefGoogle Scholar
  18. Baraniuk JN, El-Amin S, Corey R, Rayhan R, Timbol C (2013) Carnosine treatment for gulf war illness: a randomized controlled trial. Glob J Health Sci 5(3):69–81.  https://doi.org/10.5539/gjhs.v5n3p69 PubMedPubMedCentralGoogle Scholar
  19. Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, Cai J, Bhatnagar A, Srivastava S (2013) Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 33(6):1162–1170.  https://doi.org/10.1161/ATVBAHA.112.300572 PubMedGoogle Scholar
  20. Baye E, Ukropcova B, Ukropec J, Hipkiss A, Aldini G, de Courten B (2016) Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease. Amino Acids 48(5):1131–1149.  https://doi.org/10.1007/s00726-016-2208-1 PubMedGoogle Scholar
  21. Bingül İ, Yılmaz Z, Aydın AF, Çoban J, Doğru-Abbasoğlu S, Uysal M. 2017. Antiglycation and anti-oxidant efficiency of carnosine in the plasma and liver of aged rats. Geriatr Gerontol Int. doi:  https://doi.org/10.1111/ggi.13126
  22. Bispo VS, de Arruda Campos IP, Di Mascio P, Medeiros MH (2016) Structural elucidation of a carnosine-acrolein adduct and its quantification in human urine samples. Sci Rep 6(1):19348.  https://doi.org/10.1038/srep19348 PubMedPubMedCentralGoogle Scholar
  23. Boldyrev AA, Gallant SC, Sukhich GT (1999) Carnosine, the protective, anti-aging peptide. Biosci Rep 19(6):581–587.  https://doi.org/10.1023/A:1020271013277 PubMedGoogle Scholar
  24. Boldyrev A, Fedorova T, Stepanova M, Dobrotvorskaya I, Kozlova E, Boldanova N, Bagyeva G, Ivanova-Smolenskaya I, Illarioshkin S (2008) Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson’s disease: a pilot study. [Erratum appears in Rejuvenation Res. 11:988]. Rejuvenation Res 11(4):821–827.  https://doi.org/10.1089/rej.2008.0716 PubMedGoogle Scholar
  25. Boldyrev AA, Aldini G, Derave W (2013) Physiology and pathophysiology of carnosine. Physiol Rev 93(4):1803–1845.  https://doi.org/10.1152/physrev.00039.2012 PubMedGoogle Scholar
  26. Bonfanti L, Peretto P, De Marchis S, Fasolo A (1999) Carnosine-related dipeptides in the mammalian brain. Prog Neurobiol 59(4):333–353.  https://doi.org/10.1016/S0301-0082(99)00010-6 PubMedGoogle Scholar
  27. Brown BE, Kim CH, Torpy FR, Bursill CA, McRobb LS, Heather AK, Davies MJ, van Reyk DM (2014) Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(−/−) mice. Atherosclerosis 232(2):403–409.  https://doi.org/10.1016/j.atherosclerosis.2013.11.068 PubMedGoogle Scholar
  28. Cai W, Uribarri J, Zhu L, Chen X, Swamy S, Zhao Z, Grosjean F, Simonaro C, Kuchel GA, Schnaider-Beeri M, Woodward M, Striker GE, Vlassara H (2014) Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans. Proc Natl Acad Sci U S A 111(13):4940–4945.  https://doi.org/10.1073/pnas.1316013111 PubMedPubMedCentralGoogle Scholar
  29. Chaleckis R, Murakami I, Takada J, Kondoh H, Yanagida M (2016) Individual variability in human blood metabolites identifies age-related differences. Proc Natl Acad Sci U S A 113(16):4252–4259.  https://doi.org/10.1073/pnas.1603023113 PubMedPubMedCentralGoogle Scholar
  30. Chandra R, Hiniker A, Kuo YM, Nussbaum RL, Liddle RA. 2017. α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease. JCI Insight. 2. doi:  https://doi.org/10.1172/jci.insight.92295
  31. Chengappa JKN, Turkin SR, DeSanti S, Bowie SCR, Brar JS, Schlicht PJ, Murphy SL, Hetrick ML, Bilder R, Fleet D (2012) A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia. Schizophr Res 142(1-3):145–152.  https://doi.org/10.1016/j.schres.2012.10.001 PubMedGoogle Scholar
  32. Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C, Komen J (2002) Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J Child Neurol 17:833–837PubMedGoogle Scholar
  33. Chuang CH, Hu ML (2008) L-carnosine inhibits metastasis of SK-Hep-1 cells by inhibition of matrix metaoproteinase-9 expression and induction of an antimetastatic gene, nm23-H1. Nutr Cancer 60(4):526–533.  https://doi.org/10.1080/01635580801911787 PubMedGoogle Scholar
  34. Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 47(3):e147.  https://doi.org/10.1038/emm.2014.117 PubMedPubMedCentralGoogle Scholar
  35. Corona C, Frazzini V, Silvestri E, Lattanzio R, La Sorda R, Piantelli M, Canzoniero LM, Ciavardelli D, Rizzarelli E, Sensi SL (2011) Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One 6(3):e17971.  https://doi.org/10.1371/journal.pone.0017971 PubMedPubMedCentralGoogle Scholar
  36. da Silva Bispo V, Di Mascio P, Medeiros M (2014) Quantification of carnosine-aldehyde adducts in human urine. Free Radic Biol Med 75(Suppl 1):S27.  https://doi.org/10.1016/j.freeradbiomed.2014.10.751 PubMedGoogle Scholar
  37. Davies SS, Zhang LS (2017) Reactive carbonyl species scavengers—novel therapeutic approaches for chronic diseases. Curr Pharmacol Rep 3(2):51–67.  https://doi.org/10.1007/s40495-017-0081-6 PubMedPubMedCentralGoogle Scholar
  38. Davis CK, Laud PJ, Bahor Z, Rajanikant GK, Majid A (2016) Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke. J Cereb Blood Flow Metab 36(10):1686–1694.  https://doi.org/10.1177/0271678X16658302 PubMedPubMedCentralGoogle Scholar
  39. Deng Y, Zhang Y, Li Y, Xiao S, Song D, Qing H, Li Q, Rajput AH (2012) Occurrence and distribution of salsolinol-like compound, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ) in parkinsonian brains. J Neural Transm (Vienna) 119(4):435–441.  https://doi.org/10.1007/s00702-011-0724-4 Google Scholar
  40. Desai K, Wu L (2007) Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? Recent Pat Cardiovasc Drug Discov 2(2):89–99.  https://doi.org/10.2174/157489007780832498 PubMedGoogle Scholar
  41. Desai KM, Chang T, Wang H, Banigesh A, Dhar A, Liu J, Untereiner A, Wu L (2010a) Oxidative stress and aging: is methylglyoxal the hidden enemy? Can J Physiol Pharmacol 88(3):273–284.  https://doi.org/10.1139/Y10-001 PubMedGoogle Scholar
  42. Desai KM, Chang T, Wang H, Banigesh A, Dhar A, Liu J, Untereiner A, Wu L (2010b) Oxidative stress and aging: is methylglyoxal the hidden enemy? Can J Physiol Pharmacol 88(3):273–284.  https://doi.org/10.1139/Y10-001 PubMedGoogle Scholar
  43. Di Pino A, Currenti W, Urbano F, Scicali R, Piro S, Purrello F, Rabuazzo AM (2017) High intake of dietary advanced glycation end-products is associated with increased arterial stiffness and inflammation in subjects with type 2 diabetes. Nutr Metab Cardiovasc Dis 8Google Scholar
  44. Ding M, Jiao G, Shi H, Chen Y (2017) Investigations on in vitro anti-carcinogenic potential of L-carnosine in liver cancer cells. Cytotechnology.  https://doi.org/10.1007/s10616-017-0123-2
  45. Dunn L, Allen GF, Mamais A, Ling H, Li A, Duberley KE, Hargreaves IP, Pope S, Holton JL, Lees A, Heales SJ, Bandopadhyay R (2014) Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol Aging 35(5):1111–1115.  https://doi.org/10.1016/j.neurobiolaging.2013.11.001 PubMedPubMedCentralGoogle Scholar
  46. Egawa T, Tsuda S, Goto A, Ohno Y, Yokoyama S, Goto K, Hayashi T (2017) Potential involvement of dietary advanced glycation end products in impairment of skeletal muscle growth and muscle contractile function in mice. Br J Nutr 117(01):21–29.  https://doi.org/10.1017/S0007114516004591 PubMedGoogle Scholar
  47. Ejtahed HS, Angoorani P, Asghari G, Mirmiran P, Azizi F (2016) Dietary advanced glycation end products and risk of chronic kidney disease. J Ren Nutr 26(5):308–314.  https://doi.org/10.1053/j.jrn.2016.05.003 PubMedGoogle Scholar
  48. El-Ansary A, Shaker GH, El-Gezeery AR, Al-Ayadhi L (2013) The neurotoxic effect of clindamycin-induced gut bacterial imbalance and orally administered propionic acid on DNA damage assessed by the comet assay: protective potency of carnosine and carnitine. Gut Pathog 5(1):9.  https://doi.org/10.1186/1757-4749-5-9 PubMedPubMedCentralGoogle Scholar
  49. Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, Bohr VA (2017) NAD+ in aging: molecular mechanisms and translational implications. Trends Mol Med 23(10):899–916.  https://doi.org/10.1016/j.molmed.2017.08.001 PubMedGoogle Scholar
  50. Fleming TH, Theilen TM, Masania J, Wunderle M, Karimi J, Vittas S, Bernauer R, Bierhaus A, Rabbani N, Thornalley PJ, Kroll J, Tyedmers J, Nawrotzki R, Herzig S, Brownlee M, Nawroth PP (2013) Aging-dependent reduction in glyoxalase 1 delays wound healing. Gerontology 59(5):427–437.  https://doi.org/10.1159/000351628 PubMedGoogle Scholar
  51. Fujii K, Abe K, Kadooka K, Matsumoto T, Katakura Y (2017) Carnosine activates the CREB pathway in Caco-2 cells. Cytotechnology 69(3):523–527.  https://doi.org/10.1007/s10616-017-0089-0 PubMedPubMedCentralGoogle Scholar
  52. Gaur U, Tu J, Li D, Gao Y, Lian T, Sun B, Yang D, Fan X, Yang M (2017) Molecular evolutionary patterns of NAD+/Sirtuin aging signaling pathway across taxa. PLoS One 12(8):e0182306.  https://doi.org/10.1371/journal.pone.0182306 PubMedPubMedCentralGoogle Scholar
  53. Gracy RW, Talent JM, Zvaigzne AI (1998) Molecular wear and tear leads to terminal marking and the unstable isoforms of aging. J Exp Zool 282(1-2):18–27.  https://doi.org/10.1002/(SICI)1097-010X(199809/10)282:1/2<18::AID-JEZ5>3.0.CO;2-Q PubMedGoogle Scholar
  54. Gugliucci A (2017) Formation of fructose-mediated advanced glycation end products and their roles in metabolic and inflammatory diseases. Adv Nutr 8(1):54–62.  https://doi.org/10.3945/an.116.013912 PubMedPubMedCentralGoogle Scholar
  55. Hajizadeh-Zaker R, Ghajar A, Mesgarpour B, Afarideh M, Mohammadi MR, Akhondzadeh S (2017) L-carnosine as an adjunctive therapy to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol 13. doi:  https://doi.org/10.1089/cap.2017.0026
  56. Hipkiss, AR (2015) Possible benefit of dietary carnosine towards depressive disorders. Aging Dis 6(5):300–303.  https://doi.org/10.14336/AD.2014.1211 PubMedPubMedCentralGoogle Scholar
  57. Hipkiss AR (2005a) Glycation, ageing and carnosine: are carnivorous diets beneficial? Mech Ageing Dev 126(10):1034–1039.  https://doi.org/10.1016/j.mad.2005.05.002 PubMedGoogle Scholar
  58. Hipkiss AR (2005b) Could carnosine suppress zinc-mediated proteasome inhibition and neurodegeneration? Therapeutic potential of a non-toxic but non-patentable dipeptide. Biogerontology 6(2):147–149.  https://doi.org/10.1007/s10522-005-3460-z PubMedGoogle Scholar
  59. Hipkiss AR (2006) On the mechanisms of ageing suppression by dietary restriction—is persistent glycolysis the problem? Mech Ageing Dev 127(1):8–15.  https://doi.org/10.1016/j.mad.2005.09.006 PubMedGoogle Scholar
  60. Hipkiss AR (2010) NAD(+) and metabolic regulation of age-related proteoxicity: a possible role for methylglyoxal? Exp Gerontol 45(6):395–399.  https://doi.org/10.1016/j.exger.2010.03.006 PubMedGoogle Scholar
  61. Hipkiss AR (2011) Energy metabolism and ageing regulation: metabolically driven deamidation of triosephosphate isomerase may contribute to proteostatic dysfunction. Ageing Res Rev 10(4):498–502.  https://doi.org/10.1016/j.arr.2011.05.003 PubMedGoogle Scholar
  62. Hipkiss AR (2016) Activity-induced deamidation of triose-phosphate isomerase may explain the deleterious effects of excessive glucose consumption. Int J Diabetes Clin Res 3:066Google Scholar
  63. Hipkiss AR, Michaelis J, Syrris P (1995) Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent. FEBS Lett 371(1):81–85.  https://doi.org/10.1016/0014-5793(95)00849-5 PubMedGoogle Scholar
  64. Hipkiss AR, Worthington VC, Himsworth DT, Herwig W (1998a) Protective effects of carnosine against protein modification mediated by malondialdehyde and hypochlorite. Biochim Biophys Acta 1380(1):46–54.  https://doi.org/10.1016/S0304-4165(97)00123-2 PubMedGoogle Scholar
  65. Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M, Michaelis J, Lawrence J, Mateen A, Allende L, Eagles PA, Abbott NJ (1998b) Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann New York Acad Sci 854(1 TOWARDS PROLO):37–53.  https://doi.org/10.1111/j.1749-6632.1998.tb09890.x Google Scholar
  66. Hisatsune T, Kaneko J, Kurashige H, Cao Y, Satsu H, Totsuka M, Katakura Y, Imabayashi E, Matsuda H (2015) Effect of anserine/carnosine supplementation on verbal episodic memory in elderly people. J Alzheimers Dis 50(1):149–159.  https://doi.org/10.3233/JAD-150767 PubMedCentralGoogle Scholar
  67. Hoffman JR, Ostfield I, Stout JR, Harris RC, Moran DS (2015). Beta-alanine supplementation diets enhance behavioral resilience to stress exposure in an animal model of PTSD. Amino Acids 47:1247–1257.  https://doi.org/10.1007/s00726-015-1952-y
  68. Holliday R, McFarland GA (1996) Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine. Br J Cancer 73(8):966–971.  https://doi.org/10.1038/bjc.1996.189 PubMedPubMedCentralGoogle Scholar
  69. Imai SI, Guarente L (2016) It takes two to tango: NAD+ and sirtuins in aging/longevity control. NPJ Aging Mech Dis 2(1):16017.  https://doi.org/10.1038/npjamd.2016.17 PubMedPubMedCentralGoogle Scholar
  70. Inagi R (2014) Glycative stress and glyoxalase in kidney disease and aging. Biochem Soc Trans 42(2):457–460.  https://doi.org/10.1042/BST20140007 PubMedGoogle Scholar
  71. Ingram DK, Roth GS (2015) Calorie restriction mimetics: can you have your cake and eat it, too? Ageing Res Rev 20:46–62.  https://doi.org/10.1016/j.arr.2014.11.005 PubMedGoogle Scholar
  72. Iovine B, Iannella ML, Nocella F, Pricolo MR, Bevilacqua MA (2012) Carnosine inhibits KRAS-mediated HCT116 proliferation by affecting ATP and ROS production. Cancer Lett 315(2):122–128.  https://doi.org/10.1016/j.canlet.2011.07.021 PubMedGoogle Scholar
  73. Ishida YI, Kayama T, Kibune Y, Nishimoto S, Koike S, Suzuki T, Horiuchi Y, Miyashita M, Itokawa M, Arai M, Ogasawara Y (2017) Identification of an argpyrimidine-modified protein in human red blood cells from schizophrenic patients: a possible biomarker for diseases involving carbonyl stress. Biochem Biophys Res Commun 493(1):573–577.  https://doi.org/10.1016/j.bbrc.2017.08.150 PubMedGoogle Scholar
  74. Jellinger KA (2017) Multiple system atrophy: an oligodendroglioneural synucleinopathy. J Alzheimers Dis 26:1–38.  https://doi.org/10.3233/JAD-170397 CrossRefGoogle Scholar
  75. Kang JH (2012) Salsolinol, a tetrahydroisoquinoline-derived neurotoxin, induces oxidative modification of neurofilament-L protection by histidyl dipeptides. BMB Rep 45(2):114–119.  https://doi.org/10.5483/BMBRep.2012.45.2.114 PubMedGoogle Scholar
  76. Kang JH, Kim KS (2003) Enhanced oligomerization of the alpha-synuclein mutant by the Cu,Zn-superoxide dismutase and hydrogen peroxide system. Mol Cells 15(1):87–93PubMedGoogle Scholar
  77. Kardani J, Sethi R, Roy I (2017) Nicotine slows down oligomerisation of α-synuclein and ameliorates cytotoxicity in a yeast model of Parkinson’s disease. Biochim Biophys Acta 1863(6):1454–1463.  https://doi.org/10.1016/j.bbadis.2017.02.002 PubMedGoogle Scholar
  78. Killinger BA, Labrie V (2017) Vertebrate food products as a potential source of prion-like alpha-synuclein. NPJ Parkinson’s disease 3(1):33.  https://doi.org/10.1038/s41531-017-0035-z PubMedPubMedCentralGoogle Scholar
  79. Kim SR, Eom TK, Byun HG (2014) Inhibitory effect of the carnosine-gallic acid synthetic peptide on MMP-2 and MMP-9 in human fibrosarcoma HT1080 cells. J Pept Sci 20(9):716–724.  https://doi.org/10.1002/psc.2658 PubMedGoogle Scholar
  80. Kohen R, Yamamoto Y, Cundy KC, Ames BN (1988) Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci U S A 85(9):3175–3179.  https://doi.org/10.1073/pnas.85.9.3175 PubMedPubMedCentralGoogle Scholar
  81. Lombardi C, Carubelli V, Lazzarini V, Carubelli V, Vizzardi E, Bordonali T, Ciccarese C, Castrini AI, Dei Cas A, Nodari S, Metra M (2015) Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition 31(1):72–78.  https://doi.org/10.1016/j.nut.2014.04.021 PubMedGoogle Scholar
  82. Lubitz I, Ricny J, Atrakchi-Baranes D, Shemesh C, Kravitz E, Liraz-Zaltsman S, Maksin-Matveev A, Cooper I, Leibowitz A, Uribarri J, Schmeidler J, Cai W, Kristofikova Z, Ripova D, LeRoith D, Schnaider-Beeri M (2016) High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model. Aging Cell 15(2):309–316.  https://doi.org/10.1111/acel.12436 PubMedPubMedCentralGoogle Scholar
  83. Luo G, Huang B, Qiu X, Xiao L, Wang N, Gao Q, Yang W, Hao L (2017) Resveratrol attenuates excessive ethanol exposure induced insulin resistance in rats via improving NAD+ /NADH ratio. Mol Nutr Food Res. 8. doi: https://doi.org/10.1002/mnfr
  84. Ma J, Bo SH, Lu XT, Xu AJ, Zhang J (2016) Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion. Neural Regen Res 11(9):1438–1444.  https://doi.org/10.4103/1673-5374.191217 PubMedPubMedCentralCrossRefGoogle Scholar
  85. Macedo LW, Cararo JH, Maravai SG, Gonçalves CL, Oliveira GM, Kist LW, Guerra Martinez C, Kurtenbach E, Bogo MR, Hipkiss AR, Streck EL, Schuck PF, Ferreira GC (2016) Acute carnosine administration increases respiratory chain complexes and citric acid cycle enzyme activities in cerebral cortex of young rats. Mol Neurobiol 53(8):5582–5590.  https://doi.org/10.1007/s12035-015-9475-9 PubMedGoogle Scholar
  86. Marinova Z, Maercker A, Grunblatt E, Wojdacz TK, Walitza S (2017) A pilot investigation of DNA methylation modifications associated with complex posttraumatic symptoms in elderly traumatized in childhood. BMC Res Notes 10(1):752.  https://doi.org/10.1186/s13104-017-3082-y PubMedPubMedCentralGoogle Scholar
  87. Matsumoto J, Stewart T, Sheng L, Li N, Bullock K, Song N, Shi M, Banks WA, Zhang J (2017) Transmission of α-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson’s disease? Acta Neuropathol Commun 5(1):71.  https://doi.org/10.1186/s40478-017-0470-4 PubMedPubMedCentralGoogle Scholar
  88. McCarty MF, DiNicolantonio JJ (2014) β-Alanine and orotate as supplements for cardiac protection. Open Heart 1(1):e000119.  https://doi.org/10.1136/openhrt-2014-000119 PubMedPubMedCentralGoogle Scholar
  89. McFarland GA, Holliday R (1994) Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res 212(2):167–175.  https://doi.org/10.1006/excr.1994.1132 PubMedGoogle Scholar
  90. Ming X, Stein TP, Barnes V, Rhodes N, Guo L (2012) Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res 11(12):5856–5862.  https://doi.org/10.1021/pr300910n PubMedGoogle Scholar
  91. Münch G, Westcott B, Menini T, Gugliucci A (2012) Advanced glycation endproducts and their pathogenic roles in neurological disorders. Amino Acids 42(4):1221–1236.  https://doi.org/10.1007/s00726-010-0777-y PubMedGoogle Scholar
  92. Muronetz VI, Melnikova AK, Seferbekova ZN, Barinova KV, Schmalhausen EV (2017) Glycation, glycolysis, and neurodegenerative diseases: is there any connection? Biochemistry (Mosc) 82(8):874–886.  https://doi.org/10.1134/S0006297917080028 Google Scholar
  93. Nishiwaki H, Kato S, Sugamoto S, Umeda M, Morita H, Yoneta T, Takeuchi K (1999) Ulcerogenic and healing impairing actions of monochloramine in rat stomachs: effects of zinc L-carnosine, polaprezinc. J Physiol Pharmacol 50(2):183–195PubMedGoogle Scholar
  94. Ozdoğan K, Taşkın E, Dursun N (2011) Protective effect of carnosine on adriamycin-induced oxidative heart damage in rats. Anadolu Kardiyol Derg 11(1):3–10.  https://doi.org/10.5152/akd.2011.003 PubMedGoogle Scholar
  95. Pietkiewicz J, Bronowicka-Szydełko A, Dzierzba K, Danielewicz R, Gamian A (2011) Glycation of the muscle-specific enolase by reactive carbonyls: effect of temperature and the protection role of carnosine, pyridoxamine and phosphatidylserine. Protein J 30(3):149–158.  https://doi.org/10.1007/s10930-011-9307-3 PubMedGoogle Scholar
  96. Powers SK, Nelson WB, Hudson MB (2011) Exercise-induced oxidative stress in humans: cause and consequences. Free Radic Biol Med 51(5):942–950.  https://doi.org/10.1016/j.freeradbiomed.2010.12.009 PubMedGoogle Scholar
  97. Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN (1998) Toxic effects of beta-amyloid (25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Neurosci Lett 242(2):105–108.  https://doi.org/10.1016/S0304-3940(98)00058-5 PubMedGoogle Scholar
  98. Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K (2015) Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci U S A 112(38):E5308–E5317.  https://doi.org/10.1073/pnas.1514475112 PubMedPubMedCentralGoogle Scholar
  99. Rabbani N, Thornalley PJ (2012) Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids 42(4):1133–1142.  https://doi.org/10.1007/s00726-010-0783-0 PubMedGoogle Scholar
  100. Rashid I, van Reyk DM, Davies MJ (2007) Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Lett 581(5):1067–1070.  https://doi.org/10.1016/j.febslet.2007.01.082 PubMedGoogle Scholar
  101. Regazzoni L, de Courten B, Garzon D, Altomare A, Marinello C, Jakubova M, Vallova S, Krumpolec P, Carini M, Ukropec J, Ukropcova B, Aldini G (2016) A carnosine intervention study in overweight human volunteers: bioavailability and reactive carbonyl species sequestering effect. Sci Rep 6(1):27224.  https://doi.org/10.1038/srep27224 PubMedPubMedCentralGoogle Scholar
  102. Renner C, Asperger A, Seyffarth A, Meixensberger J, Gebhardt R, Gaunitz F (2010) Carnosine inhibits ATP production in cells from malignant glioma. Neurol Res 32(1):101–105.  https://doi.org/10.1179/016164109X12518779082237 PubMedGoogle Scholar
  103. Rizak JD, Ma Y, Hu X (2014) Is formaldehyde the missing link in AD pathology? The differential aggregation of amyloid-beta with APOOE isoforms in vitro. Curr Alzheimer Res 11(5):461–468PubMedGoogle Scholar
  104. Roberts PR, Black KW, Santamauro JT, Zaloga GP (1998) Dietary peptides improve wound healing following surgery. Nutrition 14(3):266–269.  https://doi.org/10.1016/S0899-9007(97)00468-1 PubMedGoogle Scholar
  105. Robinson NE, Robinson AB (2004) Molecular clocks: deamidation of asparaginyl and glutaminyl residues in peptides and proteins. Althouse Press, Oregon, p 231Google Scholar
  106. Sakae K, Yanagisawa H (2014) Oral treatment of pressure ulcers with polaprezinc (zinc L-carnosine complex): 8-week open-label trial. Biol Trace Elem Res 158(3):280–288.  https://doi.org/10.1007/s12011-014-9943-5 PubMedGoogle Scholar
  107. Sale C, Artioli GG, Gualano B, Saunders B, Hobson RM, Harris RC (2013) Carnosine: from exercise performance to health. Amino Acids 44(6):1477–1491.  https://doi.org/10.1007/s00726-013-1476-2 PubMedGoogle Scholar
  108. Semba RD, Nicklett EJ, Ferrucci L (2010) Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci 65:963–975PubMedGoogle Scholar
  109. Skovgaard D, Svensson RB, Scheijen J, Eliasson P, Mogensen P, Hag AM, Kjær M, Schalkwijk CG, Schjerling P, Magnusson SP, Couppé C (2017) An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon. Physiol Rep 5(6). doi:  https://doi.org/10.14814/phy2.13215
  110. Son DO, Satsu H, Kiso Y, Totsuka M, Shimizu M (2008) Inhibitory effect of carnosine on interleukin-8 production in intestinal epithelial cells through translational regulation. Cytokine 42(2):265–276.  https://doi.org/10.1016/j.cyto.2008.02.011 PubMedGoogle Scholar
  111. Song DW, Xin N, Xie BJ, Li YJ, Meng LY, Li HM, Schläppi M, Deng YL (2014) Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes. Int J Mol Med 33(3):736–742.  https://doi.org/10.3892/ijmm.2013.1604 PubMedGoogle Scholar
  112. Swetha MP, Muthukumar SP (2016) Characterization of nutrients, amino acids, polyphenols and antioxidant activity of Ridge gourd (Luffa acutangula) peel. J Food Sci Technol 53(7):3122–3128.  https://doi.org/10.1007/s13197-016-2285-x PubMedPubMedCentralGoogle Scholar
  113. Szcześniak D, Budzeń S, Kopeć W, Rymaszewska J (2014) Anserine and carnosine supplementation in the elderly: effects on cognitive functioning and physical capacity. Arch Gerontol Geriatr 59(2):485–490.  https://doi.org/10.1016/j.archger.2014.04.008 PubMedGoogle Scholar
  114. Tajes M, Eraso-Pichot A, Rubio-Moscardó F, Guivernau B, Ramos-Fernández E, Bosch-Morató M, Guix FX, Clarimón J, Miscione GP, Boada M, Gil-Gómez G, Suzuki T, Molina H, Villà-Freixa J, Vicente R, Muñoz FJ (2014) Methylglyoxal produced by amyloid-β peptide-induced nitrotyrosination of triosephosphate isomerase triggers neuronal death in Alzheimer's disease. J Alzheimers Dis 41(1):273–288.  https://doi.org/10.3233/JAD-131685 PubMedGoogle Scholar
  115. Tan D, Wang Y, Lo CY, Sang S, Ho CT (2008) Methylglyoxal: its presence in beverages and potential scavengers. Ann N Y Acad Sci 1126(1):72–75.  https://doi.org/10.1196/annals.1433.027 PubMedGoogle Scholar
  116. Tong Z, Han C, Qiang M, Wang W, Lv J, Zhang S, Luo W, Li H, Luo H, Zhou J, Wu B, Su T, Yang X, Wang X, Liu Y, He R, Han C, Qiang M (2015) Age-related formaldehyde interferes with DNA methyltransferase function, causing memory loss in Alzheimer’s disease. Neurobiol Aging 36(1):100–110.  https://doi.org/10.1016/j.neurobiolaging.2014.07.018 PubMedGoogle Scholar
  117. Tong Z, Wang W, Luo W, Lv J, Li H, Luo H, Jia J, He R (2016) Urine formaldehyde predicts cognitive impairment in post-stroke dementia and Alzheimer’s disease. J Alzheimers Dis 55(3):1031–1038.  https://doi.org/10.3233/JAD-160357 Google Scholar
  118. 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(21):11510–11516.  https://doi.org/10.1021/jf103258p PubMedGoogle Scholar
  119. Tulpule K, Dringen R (2012) Formate generated by cellular oxidation of formaldehyde accelerates the glycolytic flux in cultured astrocytes. Glia 60(4):582–593.  https://doi.org/10.1002/glia.22292 PubMedGoogle Scholar
  120. Tulpule K, Dringen R (2013) Formaldehyde in the brain: an overlooked player in neurodegeneration? J Neurochem 127(1):7–21.  https://doi.org/10.1111/jnc.12356 PubMedCrossRefGoogle Scholar
  121. Tulpule K, Hohnholt MC, Dringen R (2013) Formaldehyde metabolism and formaldehyde-induced stimulation of lactate and glutathione export in cultured neurons. J Neurochem 125(2):260–722.  https://doi.org/10.1111/jnc.12170 PubMedGoogle Scholar
  122. Uchiki T, Weikel KA, Jiao W, Shang F, Caceres A, Pawlak D, Handa JT, Brownlee M, Nagaraj R, Taylor A (2012) Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics). Aging Cell 11(1):1–13.  https://doi.org/10.1111/j.1474-9726.2011.00752.x PubMedGoogle Scholar
  123. Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, Yong A, Striker GE, Vlassara H (2010) Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc 110(6):911–916.  https://doi.org/10.1016/j.jada.2010.03.018 PubMedPubMedCentralGoogle Scholar
  124. Uribarri J, del Castillo MD, de la Maza MP, Filip R, Gugliucci A, Luevano-Contreras C, Macías-Cervantes MH, Markowicz Bastos DH, Medrano A, Menini T, Portero-Otin M, Rojas A, Sampaio GR, Wrobel K, Wrobel K, Garay-Sevilla ME (2015) Dietary advanced glycation end products and their role in health and disease. Adv Nutr 6(4):461–473.  https://doi.org/10.3945/an.115.008433 PubMedPubMedCentralGoogle Scholar
  125. Vicente Miranda H, El-Agnaf OM, Outeiro TF (2016) Glycation in Parkinson’s disease and Alzheimer’s disease. Mov Disord 31(6):782–790.  https://doi.org/10.1002/mds.26566 PubMedGoogle Scholar
  126. Vicente Miranda H, Cássio R, Correia-Guedes L, Gomes MA, Chegão A, Miranda E, Soares T, Coelho M, Rosa MM, Ferreira JJ, Outeiro TF (2017a) Posttranslational modifications of blood-derived alpha-synuclein as biochemical markers for Parkinson’s disease. Sci Rep 7(1):13713.  https://doi.org/10.1038/s41598-017-14175-5 PubMedPubMedCentralGoogle Scholar
  127. Vicente Miranda H, Szego ÉM, Oliveira LM, Breda C, Darendelioglu E, de Oliveira RM, Ferreira DG, Gomes MA, Rott R, Oliveira M, Munari F, Enguita FJ, Simões T, Rodrigues EF, Heinrich M, Martins IC, Zamolo I, Riess O, Cordeiro C, Ponces-Freire A, Lashuel HA, Santos NC, Lopes LV, Xiang W, Jovin TM, Penque D, Engelender S, Zweckstetter M, Klucken J, Giorgini F, Quintas A, Outeiro TF (2017b) Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. Brain 140(5):1399–1419.  https://doi.org/10.1093/brain/awx056 PubMedGoogle Scholar
  128. Vlassara H, Striker GE (2011) AGE restriction in diabetes mellitus: a paradigm shift. Nat Rev Endocrinol 7(9):526–539.  https://doi.org/10.1038/nrendo.2011.74 PubMedPubMedCentralGoogle Scholar
  129. Vlassara H, Cai W, Crandall J, Goldberg T, Oberstein R, Dardaine V, Peppa M, Rayfield EJ (2002) Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci U S A 99(24):15596–15601.  https://doi.org/10.1073/pnas.242407999 PubMedPubMedCentralGoogle Scholar
  130. West RK, Moshier E, Lubitz I, Schmeidler J, Godbold J, Cai W, Uribarri J, Vlassara H, Silverman JM, Beeri MS (2014) Dietary advanced glycation end products are associated with decline in memory in young elderly. Mech Ageing Dev 140:10–12.  https://doi.org/10.1016/j.mad.2014.07.001 PubMedPubMedCentralGoogle Scholar
  131. Xie B, Lin F, Ullah K, Peng L, Ding W, Dai R, Qing H, Deng Y (2015) A newly discovered neurotoxin ADTIQ associated with hyperglycemia and Parkinson’s disease. Biochem Biophys Res Commun 459(3):361–366.  https://doi.org/10.1016/j.bbrc.2015.02.069 PubMedGoogle Scholar
  132. Xue M, Rabbani N, Thornalley PJ (2011) Glyoxalase in ageing. Semin Cell Dev Biol 22(3):293–301.  https://doi.org/10.1016/j.semcdb.2011.02.013 PubMedGoogle Scholar
  133. Zaki MM, Abdel-Al H, Al-Sawi M (2017) Assessment of plasma amino acid profile in autism using cation-exchange chromatography with postcolumn derivatization by ninhydrin. Turk J Med Sci 47(1):260–267.  https://doi.org/10.3906/sag-1506-105 PubMedGoogle Scholar
  134. Zhang Z, Miao L, Wu X, Liu G, Peng Y, Xin X, Jiao B, Kong X (2014) Carnosine inhibits the proliferation of human gastric carcinoma cells by retarding Akt/mTOR/p70S6K signaling. J Cancer 5(5):382–389.  https://doi.org/10.7150/jca.8024 PubMedPubMedCentralGoogle Scholar
  135. Zhao J, Shi L, Zhang LR (2017) Neuroprotective effect of carnosine against salsolinol-induced Parkinson’s disease. Exp Ther Med 14(1):664–670.  https://doi.org/10.3892/etm.2017.4571 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Aston Research Centre for Healthy Ageing (ARCHA) School of Health and Life SciencesAston UniversityBirminghamUK

Personalised recommendations