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Mdivi-1 Protects Epileptic Hippocampal Neurons from Apoptosis via Inhibiting Oxidative Stress and Endoplasmic Reticulum Stress in Vitro

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An Erratum to this article was published on 16 June 2016

Abstract

Mitochondrial division inhibitor 1 (mdivi-1), a selective inhibitor of the mitochondrial fission protein dynamin-related protein 1, has been proposed to have a neuroprotective effect on hippocampal neurons in animal models of epilepsy. However, the effect of mdivi-1 on epileptic neuronal death in vitro remains unknown. Therefore, we investigated the effect of mdivi-1 and the underlying mechanisms in the hippocampal neuronal culture (HNC) model of acquired epilepsy (AE) in vitro. We found that mitochondrial fission was increased in the HNC model of AE and inhibition of mitochondrial fission by mdivi-1 significantly decreased neuronal apoptosis induced by AE. In addition, mdivi-1 pretreatment significantly attenuated oxidative stress induced by AE characterized by decrease of reactive oxygen species (ROS) production and malondialdehyde level and by increase of superoxide dismutase activity. Moreover, mdivi-1 pretreatment significantly decreased endoplasmic reticulum (ER) stress markers glucose-regulated protein 78, C/EBP homologous protein expression and caspase-3 activation. Altogether, our findings suggest that mdivi-1 protected against AE-induced hippocampal neuronal apoptosis in vitro via decreasing ROS-mediated oxidative stress and ER stress.

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References

  1. Puttachary S, Sharma S, Stark S, Thippeswamy T (2015) Seizure-induced oxidative stress in temporal lobe epilepsy. Biomed Res Int 2015:745613

    Article  PubMed  PubMed Central  Google Scholar 

  2. Paschen W, Mengesdorf T (2005) Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium 38:409–415

    Article  CAS  PubMed  Google Scholar 

  3. Yamamoto A, Murphy N, Schindler CK, So NK, Stohr S, Taki W, Prehn JH, Henshall DC (2006) Endoplasmic reticulum stress and apoptosis signaling in human temporal lobe epilepsy. J Neuropathol Exp Neurol 65:217–225

    Article  CAS  PubMed  Google Scholar 

  4. Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cao SS, Kaufman RJ (2014) Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal 21:396–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, Nunnari J (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14:193–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tanaka A, Youle RJ (2008) A chemical inhibitor of DRP1 uncouples mitochondrial fission and apoptosis. Mol Cell 29:409–410

    Article  CAS  PubMed  Google Scholar 

  8. Xie N, Wang C, Lian Y, Zhang H, Wu C, Zhang Q (2013) A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett 545:64–68

    Article  CAS  PubMed  Google Scholar 

  9. Qiu X, Cao L, Yang X, Zhao X, Liu X, Han Y, Xue Y, Jiang H, Chi Z (2013) Role of mitochondrial fission in neuronal injury in pilocarpine-induced epileptic rats. Neuroscience 245:157–165

    Article  CAS  PubMed  Google Scholar 

  10. Banker GA, Cowan WM (1977) Rat hippocampal neurons in dispersed cell culture. Brain Res 126:397–442

    Article  CAS  PubMed  Google Scholar 

  11. Blair RE, Deshpande LS, Sombati S, Elphick MR, Martin BR, DeLorenzo RJ (2009) Prolonged exposure to WIN55,212-2 causes downregulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy. Neuropharmacology 57:208–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sombati S, Delorenzo RJ (1995) Recurrent spontaneous seizure activity in hippocampal neuronal networks in culture. J Neurophysiol 73:1706–1711

    CAS  PubMed  Google Scholar 

  13. Blair RE, Deshpande LS, Sombati S, Falenski KW, Martin BR, DeLorenzo RJ (2006) Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther 317:1072–1078

    Article  CAS  PubMed  Google Scholar 

  14. Deshpande LS, Blair RE, Ziobro JM, Sombati S, Martin BR, DeLorenzo RJ (2007) Endocannabinoids block status epilepticus in cultured hippocampal neurons. Eur J Pharmacol 558:52–59

    Article  CAS  PubMed  Google Scholar 

  15. Xie N, Li H, Wei D, LeSage G, Chen L, Wang S, Zhang Y, Chi L, Ferslew K, He L, Chi Z, Yin D (2010) Glycogen synthase kinase-3 and p38 MAPK are required for opioid-induced microglia apoptosis. Neuropharmacology 59:444–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xue Y, Xie N, Cao L, Zhao X, Jiang H, Chi Z (2011) Diazoxide preconditioning against seizure-induced oxidative injury is via the PI3 K/Akt pathway in epileptic rat. Neurosci Lett 495:130–134

    Article  CAS  PubMed  Google Scholar 

  17. Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA (2003) Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol 15:706–716

    Article  CAS  PubMed  Google Scholar 

  18. Henshall DC, Simon RP (2005) Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab 25:1557–1572

    Article  CAS  PubMed  Google Scholar 

  19. Parone PA, Da Cruz S, Tondera D, Mattenberger Y, James DI, Maechler P, Barja F, Martinou JC (2008) Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3:e3257

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci 1201:34–39

    Article  CAS  PubMed  Google Scholar 

  21. Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, Graber S, Kovacs I, Lee WD, Waggoner J, Cui J, White AD, Bossy B, Martinou JC, Youle RJ, Lipton SA, Ellisman MH, Perkins GA, Bossy-Wetzel E (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 25:3900–3911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang A, Chi Z, Wang S, Sun Q (2009) Calcineurin-mediated GABA(A) receptor dephosphorylation in rats after kainic acid-induced status epilepticus. Seizure 18:519–523

    Article  PubMed  Google Scholar 

  23. Tutka P, Czuczwar SJ, Kleinrok Z (1997) Nitric oxide and seizure susceptibility in various models of epilepsy in mice. Pol J Pharmacol 49:68

    CAS  PubMed  Google Scholar 

  24. McBride HM, Neuspiel M, Wasiak S (2006) Mitochondria: more than just a powerhouse. Curr Biol 16:R551–R560

    Article  CAS  PubMed  Google Scholar 

  25. Kobashigawa S, Suzuki K, Yamashita S (2011) Ionizing radiation accelerates Drp1-dependent mitochondrial fission, which involves delayed mitochondrial reactive oxygen species production in normal human fibroblast-like cells. Biochem Biophys Res Commun 414:795–800

    Article  CAS  PubMed  Google Scholar 

  26. Yu T, Sheu SS, Robotham JL, Yoon Y (2008) Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res 79:341–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yu T, Jhun BS, Yoon Y (2011) High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission. Antioxid Redox Signal 14:425–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zanna C, Ghelli A, Porcelli AM, Karbowski M, Youle RJ, Schimpf S, Wissinger B, Pinti M, Cossarizza A, Vidoni S, Valentino ML, Rugolo M, Carelli V (2008) OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 131:352–367

    Article  PubMed  Google Scholar 

  29. Ashraf NU, Sheikh TA (2015) Endoplasmic reticulum stress and Oxidative stress in the pathogenesis of Non-alcoholic fatty liver disease. Free Radic Res 49:1405–1418

    Article  CAS  PubMed  Google Scholar 

  30. Mota SI, Costa RO, Ferreira IL, Santana I, Caldeira GL, Padovano C, Fonseca AC, Baldeiras I, Cunha C, Letra L, Oliveira CR, Pereira CM, Rego AC (2015) Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer’s disease. Biochim Biophys Acta 1852:1428–1441

    Article  CAS  PubMed  Google Scholar 

  31. Yoon DH, Kwon OY, Mang JY, Jung MJ, Kim do Y, Park YK, Heo TH, Kim SJ (2011) Protective potential of resveratrol against oxidative stress and apoptosis in Batten disease lymphoblast cells. Biochem Biophys Res Commun 414:49–52

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a grant from National Natural Science Foundation of China (No. 81,571,260, 81371438) and the Youth Innovation Found of the First Affiliated Hospital of the Zhengzhou University.

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China

    Nanchang Xie, Chuanjie Wu, Xuan Cheng, Yanlun Gao, Haifeng Zhang, Yi Zhang & Yajun Lian

  2. Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China

    Cui Wang

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  1. Nanchang Xie
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Correspondence to Yajun Lian.

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Xie, N., Wang, C., Wu, C. et al. Mdivi-1 Protects Epileptic Hippocampal Neurons from Apoptosis via Inhibiting Oxidative Stress and Endoplasmic Reticulum Stress in Vitro. Neurochem Res 41, 1335–1342 (2016). https://doi.org/10.1007/s11064-016-1835-y

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  • DOI: https://doi.org/10.1007/s11064-016-1835-y

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