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Hyperglycemia decreases preoxiredoxin-2 expression in a middle cerebral artery occlusion model


Diabetes is a major risk factor for stroke and is also associated with worsened outcomes following a stroke. Peroxiredoxin-2 exerts potent neuroprotective effects against oxidative stress. In the present study, we identified altered peroxiredoxin-2 expression in an ischemic stroke model under hyperglycemic conditions. Adult male rats were administrated streptozotocin (40 mg/kg) via intraperitoneal injection to induce diabetes. Middle cerebral artery occlusion (MCAO) was induced surgically 4 weeks after streptozotocin treatment and cerebral cortex tissues were isolated 24 hours after MCAO. Peroxiredoxin-2 expression was evaluated in the cerebral cortex of MCAO-operated animals using a proteomics approach, and was found to be decreased. In addition, the reduction in peroxiredoxin-2 levels was more severe in cerebral ischemia with diabetes compared to animals without diabetes. Reverse-transcriptase PCR and Western blot analyses confirmed the significantly reduced peroxiredoxin-2 expression in MCAO-operated animals under hyperglycemic conditions. It is an accepted fact that peroxiredoxin-2 has antioxidative activity against ischemic injury. Thus, the findings of this study suggest that a more severe reduction in peroxiredoxin-2 under hyperglycemic conditions leads to worsened brain damage during cerebral ischemia with diabetes.


  1. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001; 32(10): 2426–2432.

    Article  CAS  PubMed  Google Scholar 

  2. Kamada H, Yu F, Nito C, Chan PH. Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood-brain barrier dysfunction. Stroke 2007; 38(3): 1044–1049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Davidson JA, Parkin CG. Is hyperglycemia a causal factor in cardiovascular disease? Does proving this relationship really matter? Yes. Diabetes Care 2009; 32(2): S331–333.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med 2011; 50(5): 567–575.

    Article  CAS  PubMed  Google Scholar 

  5. Won SJ, Tang XN, Suh SW, Yenari MA, Swanson RA. Hyperglycemia promotes tissue plasminogen activator-induced hemorrhage by Increasing superoxide production. Ann Neurol 2011; 70(4): 583–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sanderson TH, Reynolds CA, Kumar R, Przyklenk K, Huttemann M. Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol 2013; 47(1): 9–23.

    Article  CAS  PubMed  Google Scholar 

  7. Kalinina EV, Chernov NN, Saprin AN. Involvement of thio-, peroxi-, and glutaredoxins in cellular redox-dependent processes. Biochemistry (Mosc) 2008; 73(13): 1493–1510.

    Article  CAS  Google Scholar 

  8. Chae HZ, Kang SW, Rhee SG. Isoforms of mammalian peroxiredoxin that reduce peroxides in presence of thioredoxin. Methods Enzymol 1999; 300: 219–226.

    Article  CAS  PubMed  Google Scholar 

  9. Chae HZ, Oubrahim H, Park JW, Rhee SG, Chock PB. Protein glutathionylation in the regulation of peroxiredoxins: a family of thiol-specific peroxidases that function as antioxidants, molecular chaperones, and signal modulators. Antioxid Redox Signal 2012; 16(6): 506–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fisher AB. Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. Antioxid Redox Signal 2011; 15(3): 831–844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Patenaude A, Murthy MR, Mirault ME. Emerging roles of thioredoxin cycle enzymes in the central nervous system. Cell Mol Life Sci 2005; 62(10): 1063–1680.

    Article  CAS  PubMed  Google Scholar 

  12. Gan Y, Ji X, Hu X, Luo Y, Zhang L, Li P, Liu X, Yan F, Vosler P, Gao Y, Stetler RA, Chen J. Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway. Antioxid Redox Signal 2012; 17(5): 719–732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen ML. Two-dimensional gel electrophoresis revealed antipsychotic drugs induced protein expression modulations in C6 glioma cells. Prog Neuropsychopharmacol Biol Psychiatry 2013; 40: 1–11.

    Article  PubMed  Google Scholar 

  14. Hu X, Weng Z, Chu CT, Zhang L, Cao G, Gao Y, Signore A, Zhu J, Hastings T, Greenamyre JT, Chen J. Peroxiredoxin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade. J Neurosci 2011; 31(1): 247–261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boulos S, Meloni BP, Arthur PG, Bojarski C, Knuckey NW. Peroxiredoxin 2 overexpression protects cortical neuronal cultures from ischemic and oxidative injury but not glutamate excitotoxicity, whereas Cu/Zn superoxide dismutase 1 overexpression protects only against oxidative injury. J Neurosci Res 2007; 85(14): 3089–3097.

    Article  CAS  PubMed  Google Scholar 

  16. Koh PO. Proteomic analysis of focal cerebral ischemic injury in male rats. J Vet Med Sci 2010; 72(2): 181–185.

    Article  CAS  PubMed  Google Scholar 

  17. Sung JH, Koh PO. Hyperglycemia aggravates decreases of PEA-15 and its two phosphorylated forms in cerebral ischemia. J Vet Med Sci 2017; 79(3): 654–660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tancrede G, Rousseau-Migneron S, Nadeau A. Long-term changes in the diabetic state induced by different doses of streptozotocin in rats. Br J Exp Pathol 1983; 64(2): 117–123.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ezquer M, Urzua CA, Montecino S, Leal K, Conget P, Ezquer F. Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. Stem Cell Res Ther 2016; 7: 42.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Oh TW, Kang SY, Park YK. Histological analysis of five organs in streptozotocin-induced diabetic rats. Kor. J. Herbology 2013; 28(6): 39–45.

    Article  Google Scholar 

  21. Wang H, Li H, Jiang X, Shi W, Shen Z, Li M. Hepcidin is directly regulated by insulin and plays an important role in iron overload in streptozotocin-induced diabetic rats. Diabetes 2014; 63(5): 1506–1518.

    Article  CAS  PubMed  Google Scholar 

  22. Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20(1): 84–91.

    Article  CAS  PubMed  Google Scholar 

  23. Gim SA, Lee SR, Shah FA, Koh PO. Curcumin attenuates the middle cerebral artery occlusion-induced reduction in γ-enolase expression in an animal model. Lab Anim Res 2015; 31(4): 198–203.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rizk NN, Rafols J, Dunbar JC. Cerebral ischemia induced apoptosis and necrosis in normal and diabetic rats. Brain Res 2005; 1053(1-2): 1–9.

    Article  CAS  PubMed  Google Scholar 

  25. Li ZG, Britton M, Sima AA, Dunbar JC. Diabetes enhances apoptosis induced by cerebral ischemia. Life Sci 2004; 76(3): 249–262.

    Article  CAS  PubMed  Google Scholar 

  26. Haskins K, Bradley B, Powers K, Fadok V, Flores S, Ling X, Pugazhenthi S, Reusch J, Kench J. Oxidative stress in type 1 diabetes. Ann N Y Acad Sci 2003; 1005: 43–54.

    Article  CAS  PubMed  Google Scholar 

  27. Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia 2002; 45(1): 85–96.

    Article  CAS  PubMed  Google Scholar 

  28. Zhao F, Wang Q. The protective effect of peroxiredoxin II on oxidative stress induced apoptosis in pancreatic β-cells. Cell Biosci 2012; 2(1): 22.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Nukatsuka M, Sakurai H, Yoshimura Y, Nishida M, Kawada J. Enhancement by streptozotocin of O2-radical generation by the xanthine oxidase system of pancreatic beta-cells. FEBS Lett 1988; 239(2): 295–298.

    Article  CAS  PubMed  Google Scholar 

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This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST)(NRF-2015RIDIAIAOI058270).

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Correspondence to Phil-Ok Koh.

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Koh, PO. Hyperglycemia decreases preoxiredoxin-2 expression in a middle cerebral artery occlusion model. Lab Anim Res 33, 98–104 (2017).

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