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Hyperglycemia aggravates decrease in alpha-synuclein expression in a middle cerebral artery occlusion model


Hyperglycemia is one of the major risk factors for stroke. Hyperglycemia can lead to a more extensive infarct volume, aggravate neuronal damage after cerebral ischemia. α-Synuclein is especially abundant in neuronal tissue, where it underlies the etiopathology of several neurodegenerative diseases. This study investigated whether hyperglycemic conditions regulate the expression of α-synuclein in middle cerebral artery occlusion (MCAO)-induced cerebral ischemic injury. Male Sprague-Dawley rats were treated with streptozotocin (40 mg/kg) via intraperitoneal injection to induce hyperglycemic conditions. MCAO were performed four weeks after streptozotocin injection to induce focal cerebral ischemia, and cerebral cortex tissues were obtained 24 hours after MCAO. We confirmed that MCAO induced neurological functional deficits and cerebral infarction, and these changes were more extensive in diabetic animals compared to non-diabetic animals. Moreover, we identified a decrease in α-synuclein after MCAO injury. Diabetic animals showed a more serious decrease in α-synuclein than non-diabetic animals. Western blot and reverse-transcription PCR analyses confirmed more extensive decreases in α-synuclein expression in MCAO-injured animals with diabetic condition than these of non-diabetic animals. It is accepted that α- synuclein modulates neuronal cell death and exerts a neuroprotective effect. Thus, the results of this study suggest that hyperglycemic conditions cause more serious brain damage in ischemic brain injuries by decreasing α-synuclein expression.


  1. 1.

    Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008; 371(9624): 1612–1623.

    CAS  Article  Google Scholar 

  2. 2.

    Jiang YF, Liu ZQ, Cui W, Zhang WT, Gong JP, Wang XM, Zhang Y, Yang MJ. Antioxidant effect of salvianolic acid B on hippocampal CA1 neurons in mice with cerebral ischemia and reperfusion injury. Chin J Integr Med 2015; 21(7): 516–522.

    CAS  Article  Google Scholar 

  3. 3.

    Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, Maier CM, Narasimhan P, Goeders CE, Chan PH. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal 2011; 14(8): 1505–1517.

    CAS  Article  Google Scholar 

  4. 4.

    Kleikers PW, Wingler K, Hermans JJ, Diebold I, Altenhöfer S, Radermacher KA, Janssen B, Görlach A, Schmidt HH. NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury. J Mol Med (Berl) 2012; 90(12): 1391–1406.

    CAS  Article  Google Scholar 

  5. 5.

    Lee WC, Wong HY, Chai YY, Shi CW, Amino N, Kikuchi S, Huang SH. Lipid peroxidation dysregulation in ischemic stroke: plasma 4-HNE as a potential biomarker? Biochem Biophys Res Commun 2012; 425(4): 842–847.

    CAS  Article  Google Scholar 

  6. 6.

    Nigam S, Schewe T. Phospholipase A(2)s and lipid peroxidation. Biochim Biophys Acta 2000; 1488(1-2): 167–181.

    CAS  Article  Google Scholar 

  7. 7.

    Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281(5381):1309–1312.

    CAS  Article  Google Scholar 

  8. 8.

    Kuribayashi Y, Yoshida K, Sakaue T, Okumura A. In vitro studies on the influence of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6yl-hy drogen phosphate] potassium salt on lipid peroxidation and phospholipase A2 activity. Arzneimittelforschung 1992; 42(9): 1072–1074.

    CAS  PubMed  Google Scholar 

  9. 9.

    Block F, Kunkel M, Sontag KH. Posttreatment with EPC-K1, an inhibitor of lipid peroxidation and of phospholipase A2 activity, reduces functional deficits after global ischemia in rats. Brain Res Bull 1995; 36(3): 257–260.

    CAS  Article  Google Scholar 

  10. 10.

    Sidhu A, Wersinger C, Vernier P. Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J 2004; 18(6): 637–647.

    CAS  Article  Google Scholar 

  11. 11.

    Zhu M, Qin ZJ, Hu D, Munishkina LA, Fink AL. Alpha-synuclein can function as an antioxidant preventing oxidation of unsaturated lipid in vesicles. Biochemistry 2006; 45(26): 8135–8142.

    CAS  Article  Google Scholar 

  12. 12.

    Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, Meaney DF, Trojanowski JQ, Lee VM. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011; 72(1): 57–71.

    CAS  Article  Google Scholar 

  13. 13.

    Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM. Pathological α-synuclein transmission initiates Parkinsonlike neurodegeneration in nontransgenic mice. Science 2012; 338(6109): 949–953.

    CAS  Article  Google Scholar 

  14. 14.

    Makoto H, Eliezer M. Alpha-synuclein in Lewy Body Disease and Alzheimer’s Disease. Brain Pathol 1999; 9: 707–720.

    Article  Google Scholar 

  15. 15.

    Newell KL, Boyer P, Gomez-Tortosa E, Hobbs W, Hedley- Whyte ET, Vonsattel JP, Hyman BT. Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury. J Neuropathol Exp Neurol 1999; 58(12): 1263–1268.

    CAS  Article  Google Scholar 

  16. 16.

    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.

    CAS  Article  Google Scholar 

  17. 17.

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

    CAS  Article  Google Scholar 

  18. 18.

    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.

    CAS  Article  Google Scholar 

  19. 19.

    Dietrich WD, Alonso O, Busto R. Moderate hyperglycemia worsens acute blood-brain barrier injury after forebrain ischemia in rats. Stroke 1993; 24(1): 111–116.

    CAS  Article  Google Scholar 

  20. 20.

    Bruno A, Liebeskind D, Hao Q, Raychev R; UCLA Stroke Investigators. Diabetes mellitus, acute hyperglycemia, and ischemic stroke. Curr Treat Options Neurol 2010; 12(6): 492–503.

    Article  Google Scholar 

  21. 21.

    Koh PO. Cerebral ischemic injury decreases α-synuclein expression in brain tissue and glutamate-exposed HT22 cells. Lab Anim Res 2017; 33(3): 244–250.

    Article  Google Scholar 

  22. 22.

    Tancrède 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.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    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  Google Scholar 

  24. 24.

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

    CAS  Article  Google Scholar 

  25. 25.

    Shah FA, Park DJ, Koh PO. Identification of Proteins Differentially Expressed by Quercetin Treatment in a Middle Cerebral Artery Occlusion Model: A Proteomics Approach. Neurochem Res 2018; 43: 1608–1623.

    CAS  Article  Google Scholar 

  26. 26.

    Ye X, Chopp M, Cui X, Zacharek A, Cui Y, Yan T, Shehadah A, Roberts C, Liu X, Lu M, Chen J. Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats. Exp Neurol 2011; 232(2): 299–308.

    CAS  Article  Google Scholar 

  27. 27.

    Ning R, Chopp M, Zacharek A, Yan T, Zhang C, Roberts C, Lu M, Chen J. Neamine induces neuroprotection after acute ischemic stroke in type one diabetic rats. Neuroscience 2014; 257: 76–85.

    CAS  Article  Google Scholar 

  28. 28.

    Alessandri JM, Guesnet P, Vancassel S, Astorg P, Denis I, Langelier B, Aïd S, Poumès-Ballihaut C, Champeil-Potokar G, Lavialle M. Polyunsaturated fatty acids in the central nervous system: evolution of concepts and nutritional implications throughout life. Reprod Nutr Dev 2004; 44(6): 509–538.

    CAS  Article  Google Scholar 

  29. 29.

    Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. The formation of highly soluble oligomers of alphasynuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 2003; 37(4): 583–595.

    CAS  Article  Google Scholar 

  30. 30.

    Qin Z, Hu D, Han S, Reaney SH, Di Monte DA, Fink AL. Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation. J Biol Chem 2007; 282(8): 5862–5870.

    CAS  Article  Google Scholar 

  31. 31.

    Kaplan B, Ratner V, Haas E. Alpha-synuclein: its biological function and role in neurodegenerative diseases. J Mol Neurosci 2003; 20(2): 83–92.

    CAS  Article  Google Scholar 

  32. 32.

    Ma QL, Chan P, Yoshii M, Uéda K. Alpha-synuclein aggregation and neurodegenerative diseases. J Alzheimers Dis 2003; 5(2): 139–148.

    CAS  Article  Google Scholar 

  33. 33.

    Lee M, Hyun D, Halliwell B, Jenner P. Effect of the overexpression of wild-type or mutant alpha-synuclein on cell susceptibility to insult. J Neurochem 2001; 76(4): 998–1009.

    CAS  Article  Google Scholar 

  34. 34.

    Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 2003; 66(8): 1499–1503.

    CAS  Article  Google Scholar 

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Correspondence to Phil-Ok Koh.

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Kang, J., Kim, D., Park, D. et al. Hyperglycemia aggravates decrease in alpha-synuclein expression in a middle cerebral artery occlusion model. Lab Anim Res 34, 195–202 (2018).

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  • α-Synuclein
  • hyperglycemia
  • MCAO