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Cinepazide maleate protects PC12 cells against oxygen–glucose deprivation-induced injury

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Abstract

Our previous study showed that cinepazide maleate (CM) was as effective and safe as mildronate in the treatment of acute ischemic stroke in a randomized, double-blind, active-controlled phase II multicenter trial, but underlying mechanism(s) is not well understood. As an extending study, here we demonstrated that CM could protect neuronal cells by affecting mitochondrial functions. PC12 cells were exposed to 2.5 h oxygen–glucose deprivation (OGD) followed by a 24 h reoxygenation, and then treated with different concentrations (1, 10, 100 μM) of CM. Among various concentrations, 10 μM CM exhibited most significant protection on PC12 cells against OGD injury. CM was found to suppress OGD-induced oxidative stress, as supported by its capability of reducing intracellular reactive oxygen species and malondialdehyde production and enhancing superoxide dismutase activity. Importantly, our results showed that CM could preserve mitochondrial functions, as revealed by its capability of stabilizing mitochondrial membrane potential, improving OGD-induced suppression of mitochondrial respiratory complex activities and enhancing ATP production. In summary, our present study provides the first evidence that CM can protect neuronal cells against OGD injury by preserving mitochondrial functions.

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References

  1. Hirohashi M, Hagihara Y (1979) Effect of 1-[(1-pyrrolidynylcarbonyl) methyl]-4-(3, 4, 5-trimethoxycinnamoyl)piperazine maleate (cinepazide) on cerebral and peripheral circulation in cats (author’s transl). Nihon Yakurigaku Zasshi 75(5):495–506

    Article  CAS  PubMed  Google Scholar 

  2. Moritoki H, Takei M, Fujita S, Ishida Y, Akashi A (1980) Interaction of cinepazide with adenosine on guinea-pig atria. Arch Int Pharmacodyn Ther 248(2):212–224

    CAS  PubMed  Google Scholar 

  3. Muramatsu I, Sakakibara Y, Hong SC, Fujiwara M (1984) Effects of cinepazide on the purinergic responses in the dog cerebral artery. Pharmacology 28(1):27–33

    Article  CAS  PubMed  Google Scholar 

  4. Zhu Y, Zhang G, Zhao J, Li D, Yan X, Liu J, Liu X, Zhao H, Xia J, Zhang X, Li Z, Zhang B, Guo Z, Feng L, Zhang Z, Qu F, Zhao G (2013) Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial. Clin Drug Investig 33(10):755–760

    Article  CAS  PubMed  Google Scholar 

  5. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67(2):181–198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Serteser M, Ozben T, Gumuslu S, Balkan S, Balkan E (2002) The effects of NMDA receptor antagonist MK-801 on lipid peroxidation during focal cerebral ischemia in rats. Prog Neuropsychopharmacol Biol Psychiatry 26(5):871–877

    Article  CAS  PubMed  Google Scholar 

  7. Xu L, Sun J, Lu R, Ji Q, Xu JG (2005) Effect of glutamate on inflammatory responses of intestine and brain after focal cerebral ischemia. World J Gastroenterol 11(5):733–736

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Gundimeda U, McNeill TH, Elhiani AA, Schiffman JE, Hinton DR, Gopalakrishna R (2012) Green tea polyphenols precondition against cell death induced by oxygen–glucose deprivation via stimulation of laminin receptor, generation of reactive oxygen species, and activation of protein kinase Cepsilon. J Biol Chem 287(41):34694–34708

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Larsen EC, Hatcher JF, Adibhatla RM (2007) Effect of tricyclodecan-9-yl potassium xanthate (D609) on phospholipid metabolism and cell death during oxygen–glucose deprivation in PC12 cells. Neuroscience 146(3):946–961

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S (2003) Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34(3):745–751

    Article  PubMed  Google Scholar 

  12. Cen J, Liu L, He L, Liu M, Wang CJ, Ji BS (2012) N(1)-(quinolin-2-ylmethyl)butane-1,4-diamine, a polyamine analogue, attenuated injury in in vitro and in vivo models of cerebral ischemia. Int J Dev Neurosci 30(7):584–595

    Article  CAS  PubMed  Google Scholar 

  13. Zhao Y, Wang B, Gao Y, Xiao Z, Zhao W, Chen B, Wang X, Dai J (2007) Olfactory ensheathing cell apoptosis induced by hypoxia and serum deprivation. Neurosci Lett 421(3):197–202

    Article  CAS  PubMed  Google Scholar 

  14. Rodrigo R, Fernandez-Gajardo R, Gutierrez R, Matamala JM, Carrasco R, Miranda-Merchak A, Feuerhake W (2013) Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets 12(5):698–714

    Article  CAS  PubMed  Google Scholar 

  15. Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T (2005) Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke 36(10):2220–2225

    Article  CAS  PubMed  Google Scholar 

  16. Warner DS, Sheng H, Batinic-Haberle I (2004) Oxidants, antioxidants and the ischemic brain. J Exp Biol 207(Pt 18):3221–3231

    Article  CAS  PubMed  Google Scholar 

  17. Iijima T (2006) Mitochondrial membrane potential and ischemic neuronal death. Neurosci Res 55(3):234–243

    Article  CAS  PubMed  Google Scholar 

  18. Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8(2):115–128

    Article  CAS  PubMed  Google Scholar 

  19. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552(Pt 2):335–344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Moro MA, Almeida A, Bolanos JP, Lizasoain I (2005) Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 39(10):1291–1304

    Article  CAS  PubMed  Google Scholar 

  21. Drose S, Brandt U (2012) Molecular mechanisms of superoxide production by the mitochondrial respiratory chain. Adv Exp Med Biol 748:145–169

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Ms. Dongyun Feng and Ms. Rui Wu for the technique support. This work was supported by the National Natural Science Foundation of China (Nos. 31170801 and 81371365) and by Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1053).

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Correspondence to Ming Shi or Gang Zhao.

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J. Zhao and Y. Bai contributed equally to this work.

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Zhao, J., Bai, Y., Zhang, C. et al. Cinepazide maleate protects PC12 cells against oxygen–glucose deprivation-induced injury. Neurol Sci 35, 875–881 (2014). https://doi.org/10.1007/s10072-013-1618-z

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  • DOI: https://doi.org/10.1007/s10072-013-1618-z

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