Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 11, pp 1237–1245 | Cite as

Enhancement of glyoxalase 1, a polyfunctional defense enzyme, by quercetin in the brain in streptozotocin-induced diabetic rats

  • Xia Zhu
  • Ya-qin Cheng
  • Qian Lu
  • Lei Du
  • Xiao-xing YinEmail author
  • Yao-wu LiuEmail author
Original Article


Glyoxalase 1 (Glo-1) is an ubiquitous cellular enzyme that participates in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis that induces protein modification (advanced glycation end products [AGEs]), oxidative stress, and inflammation. The concentration of MG is elevated under high-glucose conditions, such as diabetes. Therefore, Glo-1 and MG have been implicated in the pathogenesis of diabetic encephalopathy. We investigated the effect of quercetin on brain damage that was caused by diabetes in rats and the mechanisms associated with Glo-1. Streptozotocin-induced diabetic rats were treated orally with quercetin (30, 60, and 90 mg/kg) or distilled water for 14 weeks. The temporal cortex and hippocampus were harvested and analyzed for different indices assays. Quercetin, especially at a high dose, increased the levels of reduced glutathione and the activity of superoxide dismutase and decreased the levels of AGEs, the receptor for AGEs (RAGE), and malondialdehyde in the diabetic brain. Quercetin also significantly decreased the levels of inflammatory markers (cyclooxygenase-2, interleukin-1β, and tumor necrosis factor α) in diabetic brains. Most importantly, Glo-1 activity and protein expression were increased in quercetin-treated diabetic rat brains compared with untreated diabetic brains. These results indicate that quercetin exerts beneficial effects by decreasing protein glycation, oxidative stress, and inflammation through the upregulation of Glo-1, which may ameliorate diabetic encephalopathy.


Diabetic encephalopathy Quercetin Glyoxalase 1 AGEs Oxidative stress Inflammation 


Author contribution

LY and YX conceived and designed research. ZX and LY were responsible for the data analysis and draft of the manuscript. ZX, CY, and LQ contributed to the acquisition of animal data. DL was responsible for purchasing reagents. All authors read and approved the manuscript.

Funding information

The work was supported through funding from the National Natural Science Foundation of China (81371210), China, and the Priority Academic Program Development of Jiangsu Higher Education Institutions, China.

Compliance with ethical standards

All animal experiments were performed in accordance with the license by Jiangsu Province Science and Technology Office (Nanjing, China) and the approval from the Animal Ethics Committee of Xuzhou Medical University (2014008). All experiments were conformed to the Guidelines for Ethical Conduct in the Care and Use of Animals. Every effort was made to minimize stress to the animals.

Conflict of interest

The authors have declared that there is no conflict of interest.


  1. Alam MM, Ahmad I, Naseem I (2015) Inhibitory effect of quercetin in the formation of advance glycation end products of human serum albumin: an in vitro and molecular interaction study. Int J Biol Macromol 79:336–343. CrossRefPubMedGoogle Scholar
  2. Anjaneyulu M, Chopra K (2004a) Quercetin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats. Indian J Exp Biol 42(8):766–769PubMedGoogle Scholar
  3. Anjaneyulu M, Chopra K (2004b) Quercetin, an anti-oxidant bioflavonoid, attenuates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol 31(4):244–248CrossRefGoogle Scholar
  4. Anjaneyulu M, Chopra K, Kaur I (2003) Antidepressant activity of quercetin, a bioflavonoid, in streptozotocin-induced diabetic mice. J Med Food 6(4):391–395CrossRefGoogle Scholar
  5. Annapurna A, Reddy CS, Akondi RB, Rao SR (2009) Cardioprotective actions of two bioflavonoids, quercetin and rutin, in experimental myocardial infarction in both normal and streptozotocin-induced type I diabetic rats. J Pharm Pharmacol 61(10):1365–1374. CrossRefPubMedGoogle Scholar
  6. Beisswenger PJ, Howell SK, Touchette AD, Lal S, Szwergold BS (1999) Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 48(1):198–202CrossRefGoogle Scholar
  7. Bhutada P, Mundhada Y, Bansod K, Bhutada C, Tawari S, Dixit P, Mundhada D (2010) Ameliorative effect of quercetin on memory dysfunction in streptozotocin-induced diabetic rats. Neurobiol Learn Mem 94(3):293–302. CrossRefPubMedGoogle Scholar
  8. Biessels GJ, van der Heide LP, Kamal A, Bleys RL, Gispen WH (2002) Ageing and diabetes: implications for brain function. Eur J Pharmacol 441(1–2):1–14CrossRefGoogle Scholar
  9. Bronner C, Landry Y (1985) Kinetics of the inhibitory effect of flavonoids on histamine secretion from mast cells. Agents Actions 16(3–4):147–151CrossRefGoogle Scholar
  10. Brouwers O, Niessen PM, Ferreira I, Miyata T, Scheffer PG, Teerlink T, Schrauwen P, Brownlee M, Stehouwer CD, Schalkwijk CG (2011) Overexpression of glyoxalase-I reduces hyperglycemia-induced levels of advanced glycation end products and oxidative stress in diabetic rats. J Biol Chem 286(2):1374–1380. CrossRefPubMedGoogle Scholar
  11. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820CrossRefGoogle Scholar
  12. Calcutt NA, Cooper ME, Kern TS, Schmidt AM (2009) Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov 8(5):417–429. CrossRefPubMedGoogle Scholar
  13. de Whalley CV, Rankin SM, Hoult JR, Jessup W, Leake DS (1990) Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages. Biochem Pharmacol 39(11):1743–1750CrossRefGoogle Scholar
  14. Di Loreto S, Caracciolo V, Colafarina S, Sebastiani P, Gasbarri A, Amicarelli F (2004) Methylglyoxal induces oxidative stress-dependent cell injury and up-regulation of interleukin-1beta and nerve growth factor in cultured hippocampal neuronal cells. Brain Res 1006(2):157–167CrossRefGoogle Scholar
  15. Di Loreto S, Zimmitti V, Sebastiani P, Cervelli C, Falone S, Amicarelli F (2008) Methylglyoxal causes strong weakening of detoxifying capacity and apoptotic cell death in rat hippocampal neurons. Int J Biochem Cell Biol 40(2):245–257CrossRefGoogle Scholar
  16. Hansen F, Pandolfo P, Galland F, Torres FV, Dutra MF, Batassini C, Guerra MC, Leite MC, Gonçalves CA (2016) Methylglyoxal can mediate behavioral and neurochemical alterations in rat brain. Physiol Behav 164(Pt A):93–101. CrossRefPubMedGoogle Scholar
  17. Hasanein P, Shahidi S (2010) Effects of combined treatment with vitamins C and E on passive avoidance learning and memory in diabetic rats. Neurobiol Learn Mem 93(4):472–478. CrossRefPubMedGoogle Scholar
  18. Karachalias N, Babaei-Jadidi R, Rabbani N, Thornalley PJ (2010) Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia 53(7):1506–1516. CrossRefPubMedGoogle Scholar
  19. Karuppagounder V, Arumugam S, Thandavarayan RA, Pitchaimani V, Sreedhar R, Afrin R, Harima M, Suzuki H, Nomoto M, Miyashita S, Suzuki K, Nakamura M, Watanabe K (2015) Modulation of HMGB1 translocation and RAGE/NFkappaB cascade by quercetin treatment mitigates atopic dermatitis in NC/Nga transgenic mice. Exp Dermatol 24(6):418–423. CrossRefPubMedGoogle Scholar
  20. Kaul TN, Middleton E Jr, Ogra PL (1985) Antiviral effect of flavonoids on human viruses. J Med Virol 15(1):71–79CrossRefGoogle Scholar
  21. Kim KM, Kim YS, Jung DH, Lee J, Kim JS (2012) Increased glyoxalase I levels inhibit accumulation of oxidative stress and an advanced glycation end product in mouse mesangial cells cultured in high glucose. Exp Cell Res 318(2):152–159. CrossRefPubMedGoogle Scholar
  22. Kuhad A, Bishnoi M, Tiwari V, Chopra K (2009) Suppression of NF-kappabeta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav 92(2):251–259. CrossRefPubMedGoogle Scholar
  23. Kuhad A, Chopra K (2007) Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences. Eur J Pharmacol 576(1–3):34–42CrossRefGoogle Scholar
  24. Kumar A, Sehgal N, Kumar P, Padi SS, Naidu PS (2008) Protective effect of quercetin against ICV colchicine-induced cognitive dysfunctions and oxidative damage in rats. Phytother Res 22(12):1563–1569. CrossRefPubMedGoogle Scholar
  25. Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Li X, Zheng T, Sang S, Lv L (2014) Quercetin inhibits advanced glycation end product formation by trapping methylglyoxal and glyoxal. J Agric Food Chem 62(50):12152–12158. CrossRefPubMedGoogle Scholar
  27. Liu J, Yu H, Ning X (2006) Effect of quercetin on chronic enhancement of spatial learning and memory of mice. Sci China C Life Sci 49(6):583–590CrossRefGoogle Scholar
  28. Liu YW, Zhu X, Li W, Lu Q, Wang JY, Wei YQ, Yin XX (2012) Ginsenoside Re attenuates diabetes-associated cognitive deficits in rats. Pharmacol Biochem Behav 101(1):93–98. CrossRefPubMedGoogle Scholar
  29. Liu YW, Zhu X, Yang QQ, Lu Q, Wang JY, Li HP, Wei YQ, Yin JL, Yin XX (2013a) Suppression of methylglyoxal hyperactivity by mangiferin can prevent diabetes-associated cognitive decline in rats. Psychopharmacology 228(4):585–594. CrossRefPubMedGoogle Scholar
  30. Liu YW, Zhu X, Zhang L, Lu Q, Wang JY, Zhang F, Guo H, Yin JL, Yin XX (2013b) Up-regulation of glyoxalase 1 by mangiferin prevents diabetic nephropathy progression in streptozotocin-induced diabetic rats. Eur J Pharmacol 721(1–3):355–364. CrossRefPubMedGoogle Scholar
  31. Liu YW, Zhu X, Zhang L, Lu Q, Zhang F, Guo H, Yin XX (2014) Cerebroprotective effects of ibuprofen on diabetic encephalopathy in rats. Pharmacol Biochem Behav 117:128–136. CrossRefPubMedGoogle Scholar
  32. Liu YW, Zhang L, Li Y, Cheng YQ, Zhu X, Zhang F, Yin XX (2016a) Activation of mTOR signaling mediates the increased expression of AChE in high glucose condition: in vitro and in vivo evidences. Mol Neurobiol 53(7):4972–4980. CrossRefPubMedGoogle Scholar
  33. Liu YW, Zhu X, Cheng YQ, Lu Q, Zhang F, Guo H, Yin XX (2016b) Ibuprofen attenuates nephropathy in streptozotocin-induced diabetic rats. Mol Med Rep 13(6):5326–5334. CrossRefPubMedGoogle Scholar
  34. Lu J, Randell E, Han Y, Adeli K, Krahn J, Meng QH (2011) Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin Biochem 44:307–311. CrossRefPubMedGoogle Scholar
  35. Lu Q, Ji XJ, Zhou YX, Yao XQ, Liu YQ, Zhang F, Yin XX (2015) Quercetin inhibits the mTORC1/p70S6K signaling-mediated renal tubular epithelial-mesenchymal transition and renal fibrosis in diabetic nephropathy. Pharmacol Res 99:237–247. CrossRefPubMedGoogle Scholar
  36. Maciel RM, Carvalho FB, Olabiyi AA, Schmatz R, Gutierres JM, Stefanello N, Zanini D, Rosa MM, Andrade CM, Rubin MA, Schetinger MR, Morsch VM, Danesi CC, Lopes STA (2016) Neuroprotective effects of quercetin on memory and anxiogenic-like behavior in diabetic rats: role of ectonucleotidases and acetylcholinesterase activities. Biomed Pharmacother 84:559–568. CrossRefPubMedGoogle Scholar
  37. Maher P, Dargusch R, Ehren JL, Okada S, Sharma K, Schubert D (2011) Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One 6(6):e21226. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Mahesh T, Menon VP (2004) Quercetin allievates oxidative stress in streptozotocin-induced diabetic rats. Phytother Res 18(2):123–127CrossRefGoogle Scholar
  39. McCall AL (2004) Cerebral glucose metabolism in diabetes mellitus. Eur J Pharmacol 490(1–3):147–158CrossRefGoogle Scholar
  40. Nowotny K, Jung T, Hohn A, Weber D, Grune T (2015) Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 5(1):194–222. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Rabbani N, Thornalley PJ (2008) Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress. Biochem Soc Trans 36(Pt 5):1045–1050. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Rabbani N, Thornalley PJ (2014) The critical role of methylglyoxal and glyoxalase 1 in diabetic nephropathy. Diabetes 63(1):50–52. CrossRefPubMedGoogle Scholar
  43. Ramana BV, Kumar VV, Krishna PN, Kumar CS, Reddy PU, Raju TN (2006) Effect of quercetin on galactose-induced hyperglycaemic oxidative stress in hepatic and neuronal tissues of Wistar rats. Acta Diabetol 43(4):135–141CrossRefGoogle Scholar
  44. Reagan LP, Magarinos AM, Yee DK, Swzeda LI, Van Bueren A, McCall AL, McEwen BS (2000) Oxidative stress and HNE conjugation of GLUT3 are increased in the hippocampus of diabetic rats subjected to stress. Brain Res 862(1–2):292–300CrossRefGoogle Scholar
  45. Reynolds RM, Strachan MW, Labad J, Lee AJ, Frier BM, Fowkes FG, Mitchell R, Seckl JR, Deary IJ, Walker BR, Price JF (2010) Morning cortisol levels and cognitive abilities in people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care 33(4):714–720. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L (2001) The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev 17(3):189–212CrossRefGoogle Scholar
  47. Roslan J, Giribabu N, Karim K, Salleh N (2017) Quercetin ameliorates oxidative stress, inflammation and apoptosis in the heart of streptozotocin-nicotinamide-induced adult male diabetic rats. Biomed Pharmacother 86:570–582. CrossRefPubMedGoogle Scholar
  48. Sena CM, Matafome P, Crisostomo J, Rodrigues L, Fernandes R, Pereira P, Seiça RM (2012) Methylglyoxal promotes oxidative stress and endothelial dysfunction. Pharmacol Res 65(5):497–506. CrossRefPubMedGoogle Scholar
  49. Shinohara M, Thornalley PJ, Giardino I, Beisswenger P, Thorpe SR, Onorato J, Brownlee M (1998) Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J Clin Invest 101(5):1142–1147CrossRefGoogle Scholar
  50. Sima AA (2010) Encephalopathies: the emerging diabetic complications. Acta Diabetol 47(4):279–293. CrossRefPubMedGoogle Scholar
  51. Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34(3):497–500PubMedGoogle Scholar
  52. Thornalley PJ (2003) Glyoxalase I--structure, function and a critical role in the enzymatic defence against glycation. Biochem Soc Trans 31(Pt 6):1343–1348CrossRefGoogle Scholar
  53. Thornalley PJ (2005) Dicarbonyl intermediates in the maillard reaction. Ann N Y Acad Sci 1043:111–117CrossRefGoogle Scholar
  54. Thornalley PJ (2007) Endogenous alpha-oxoaldehydes and formation of protein and nucleotide advanced glycation endproducts in tissue damage. Novartis Found Symp 285:229–243CrossRefGoogle Scholar
  55. Tota S, Awasthi H, Kamat PK, Nath C, Hanif K (2010) Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 209(1):73–79. CrossRefPubMedGoogle Scholar
  56. van den Berg E, Kloppenborg RP, Kessels RP, Kappelle LJ, Biessels GJ (2009) Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: a systematic comparison of their impact on cognition. Biochim Biophys Acta 1792(5):470–481. CrossRefGoogle Scholar
  57. van Deutekom AW, Niessen HW, Schalkwijk CG, Heine RJ, Simsek S (2008) Increased Nepsilon-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus. Eur J Endocrinol 158(5):655–660. CrossRefPubMedGoogle Scholar
  58. Vlassara H (1997) Recent progress in advanced glycation end products and diabetic complications. Diabetes 46(Suppl 2):S19–S25CrossRefGoogle Scholar
  59. Wang SH, Sun ZL, Guo YJ, Yuan Y, Yang BQ (2009) Diabetes impairs hippocampal function via advanced glycation end product mediated new neuron generation in animals with diabetes-related depression. Toxicol Sci 111(1):72–79. CrossRefPubMedGoogle Scholar
  60. Wrighten SA, Piroli GG, Grillo CA, Reagan LP (2009) A look inside the diabetic brain: contributors to diabetes-induced brain aging. Biochim Biophys Acta 1792(5):444–453. CrossRefPubMedGoogle Scholar
  61. Yao D, Brownlee M (2010) Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59(1):249–255. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouChina
  2. 2.Department of PharmacyTaizhou People’s HospitalTaizhouChina
  3. 3.Department of Pharmacology, School of PharmacyXuzhou Medical UniversityXuzhouChina

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