Enhancement of glyoxalase 1, a polyfunctional defense enzyme, by quercetin in the brain in streptozotocin-induced diabetic rats
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.
KeywordsDiabetic encephalopathy Quercetin Glyoxalase 1 AGEs Oxidative stress Inflammation
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.
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.
- 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. https://doi.org/10.1211/jpp/61.10.0014 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1074/jbc.M110.144097 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1007/s00125-010-1722-z CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1111/exd.12685 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.yexcr.2011.10.013 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.ejphar.2013.08.029 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.phrs.2015.06.006 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.biopha.2016.09.069 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.2337/dc09-1796 CrossRefPubMedPubMedCentralGoogle Scholar
- 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
- 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
- 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. https://doi.org/10.1016/j.bbadis.2008.09.004 CrossRefGoogle Scholar
- 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. https://doi.org/10.1530/EJE-08-0024 CrossRefPubMedGoogle Scholar