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Hyperglycemia exacerbates downregulation of dynamin-like protein 1 in ischemic cerebral injury

Laboratory Animal Research volume 33, pages 202–208 (2017)Cite this article

Abstract

Ischemic stroke is one of the leading causes of adult disability and death. Hyperglycemia is associated with an increased risk of stroke and poor outcomes after brain injury. Dynamin-like protein I (DLP-1) regulates mitochondrial fission and promotes mitochondrial dynamics. Neurodegenerative diseases are associated with mitochondrial dysfunction, and the downregulation of DLP-1 has been previously identified in a stroke animal model. Here, we investigated the changes in DLP-1 protein expression in an animal model of focal cerebral ischemia with induced hyperglycemia. Streptozotocin (40 mg/kg) was intraperitoneally injected into male rats to induce hyperglycemia, and middle cerebral artery occlusion (MCAO) was surgically induced 4 weeks after streptozotocin treatment. Brain tissue was isolated 24 hours after MCAO, and cerebral cortex samples were used for this study. Proteomics revealed a decrease in DLP-1 expression in MCAO animals when compared with controls, and this downregulation was more prominent in MCAO animals with hyperglycemia. Reverse-transcription polymerase chain reaction and Western blot analyses confirmed that DLP-1 was significantly downregulated in MCAO-injured animals with hyperglycemia compared to those without hyperglycemia. The decrease in DLP-1 indicates mitochondrial morphological changes and dysfunction. Together, these results suggest that the severe decrease of DLP-1 seen after brain injury under hyperglycemic conditions may exacerbate the damage to the brain.

References

  1. Siniscalchi A, Gallelli L, Malferrari G, Pirritano D, Serra R, Santangelo E, De Sarro G. Cerebral stroke injury: the role of cytokines and brain inflammation. J Basic Clin Physiol Pharmacol 2014; 25(2): 131–137.

    Article  CAS  PubMed  Google Scholar 

  2. Doi Y, Ninomiya T, Hata J, Fukuhara M, Yonemoto K, Iwase M, Iida M, Kiyohara Y. Impact of glucose tolerance status on development of ischemic stroke and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 2010

    Google Scholar 

  3. 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  PubMed  PubMed Central  Google Scholar 

  4. Widmer H, Abiko H, Faden AI, James TL, Weinstein PR. Effects of hyperglycemia on the time course of changes in energy metabolism and pH during global cerebral ischemia and reperfusion in rats: correlation of 1H and 31P NMR spectroscopy with fatty acid and excitatory amino acid levels. J Cereb Blood Flow Metab 1992; 12(3): 456–468.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. Folbergrová J, Memezawa H, Smith ML, Siesjö BK. Focal and perifocal changes in tissue energy state during middle cerebral artery occlusion in normo- and hyperglycemic rats. J Cereb Blood Flow Metab 1992; 12(1): 25–33.

    Article  PubMed  Google Scholar 

  7. Gentile NT, Seftchick MW, Huynh T, Kruus LK, Gaughan J. Decreased mortality by normalizing blood glucose after acute ischemic stroke. Acad Emerg Med 2006; 13(2): 174–180.

    Article  PubMed  Google Scholar 

  8. Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta 2010; 1802(1): 80–91.

    Article  CAS  PubMed  Google Scholar 

  9. Starkov AA, Chinopoulos C, Fiskum G. Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 2004; 36(3-4): 257–264.

    Article  CAS  PubMed  Google Scholar 

  10. Verstreken P, Ly C V, Venken KJ, Koh TW, Zhou Y, Bellen HJ. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 2005; 47(3): 365–378.

    Article  CAS  PubMed  Google Scholar 

  11. Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 2010; 11(12): 872–884.

    Article  CAS  PubMed  Google Scholar 

  12. Palmer CS, Osellame LD, Stojanovski D, Ryan MT. The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery. Cell Signal 2011; 23(10): 1534–1545.

    Article  CAS  PubMed  Google Scholar 

  13. Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum Mol Genet 2011; 20(7): 1438–1455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Swerdlow RH. The neurodegenerative mitochondriopathies. J Alzheimers Dis 2009; 17(4): 737–751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R, McNay EC, Yu T, Schwarzenbacher R, Bossy B, Bossy-Wetzel E, Bennett M V, Pypaert M, Hickman JA, Smith PJ, Hardwick JM, Jonas EA. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A 2008; 105(6): 2169–2174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO, Masuda K, Otera H, Nakanishi Y, Nonaka I, Goto Y, Taguchi N, Morinaga H, Maeda M, Takayanagi R, Yokota S, Mihara K. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 2009; 11(8): 958–966.

    Article  CAS  PubMed  Google Scholar 

  17. Wakabayashi J, Zhang Z, Wakabayashi N, Tamura Y, Fukaya M, Kensler TW, Iijima M, Sesaki H. The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J Cell Biol 2009; 186(6): 805–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jang AR, Koh PO. Ischemic brain injury decreases dynamin-like protein 1 expression in a middle cerebral artery occlusion animal model and glutamate-exposed HT22 cells. Lab Anim Res 2016; 32(4): 194–199.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. Jeon SJ, Sung JH, Koh PO. Hyperglycemia decreases expression of 14-3-3 proteins in an animal model of stroke. Neurosci Lett 2016; 626: 13–18.

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. 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 

  23. Low PA, Lagerlund TD, McManis PG. Nerve blood flow and oxygen delivery in normal, diabetic, and ischemic neuropathy. Int Rev Neurobiol 1989; 31: 355–438.

    Article  CAS  PubMed  Google Scholar 

  24. Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL. Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis 1999; 6(5): 347–363.

    Article  CAS  PubMed  Google Scholar 

  25. Cameron NE, Cotter MA. Effects of evening primrose oil treatment on sciatic nerve blood flow and endoneurial oxygen tension in streptozotocin-diabetic rats. Acta Diabetol 1994; 31(4): 220–225.

    Article  CAS  PubMed  Google Scholar 

  26. Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A 2006; 103(8): 2653–2658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pitts KR, Yoon Y, Krueger EW, McNiven MA. The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Mol Biol Cell 1999; 10(12): 4403–4417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Smirnova E, Shurland DL, Ryazantsev SN, van de. Bliek AM. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 1998; 143(2): 351–358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen H, Chan DC. Mitochondrial dynamics—fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet 2009; 18: 169–176.

    Article  Google Scholar 

  30. Ding C, He Q, Li PA. Activation of cell death pathway after a brief period of global ischemia in diabetic and non-diabetic animals. Exp Neurol 2004; 188(2): 421–429.

    Article  CAS  PubMed  Google Scholar 

  31. Muranyi M, Fujioka M, He Q, Han A, Yong G, Csiszar K, Li PA. Diabetes activates cell death pathway after transient focal cerebral ischemia. Diabetes 2003; 52(2): 481–486.

    Article  CAS  PubMed  Google Scholar 

  32. Muranyi M, Ding C, He Q, Lin Y, Li PA. Streptozotocin-induced diabetes causes astrocyte death after ischemia and reperfusion injury. Diabetes 2006; 55(2): 349–355.

    Article  CAS  PubMed  Google Scholar 

  33. Tiwari BS, Belenghi B, Levine A. Oxidative stress increased respiration and generation of reactive oxygen species, resulting in ATP depletion, opening of mitochondrial permeability transition, and programmed cell death. Plant Physiol 2002; 128(4): 1271–1281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Johri A, Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 2012; 342(3): 619–630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kumari S, Anderson L, Farmer S, Mehta SL, Li PA. Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected to cerebral ischemia and reperfusion. Transl Stroke Res 2012; 3(2): 296–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy, College of Veterinary Medicine, Gyeongsang National University, 501 Jinjudaero, Jinju, 52828, Korea

    Dong-Ju Park & Phil-Ok Koh

  2. Division of Life Science and Applied Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Korea

    Myeong-Ok Kim

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  1. Dong-Ju Park
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Correspondence to Phil-Ok Koh.

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Park, DJ., Kim, MO. & Koh, PO. Hyperglycemia exacerbates downregulation of dynamin-like protein 1 in ischemic cerebral injury. Lab Anim Res 33, 202–208 (2017). https://doi.org/10.5625/lar.2017.33.3.202

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Keywords

Laboratory Animal Research

ISSN: 2233-7660