Diazoxide inhibits of ER stress‑mediated apoptosis during oxygen‑glucose deprivation in vitro and cerebral ischemia‑reperfusion in vivo

Lei,Xiaofeng; Lei,Lijian; Zhang,Zhiqing; Cheng,Yan

doi:10.3892/mmr.2018.8925

Diazoxide inhibits of ER stress‑mediated apoptosis during oxygen‑glucose deprivation in vitro and cerebral ischemia‑reperfusion in vivo

Authors:
- Xiaofeng Lei
- Lijian Lei
- Zhiqing Zhang
- Yan Cheng
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Affiliations: Department of Neurology Medicine, Tianjin 4th Center Hospital, Tianjin, Hebei 300052, P.R. China, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of Neurology Medicine, Tianjin Medical University General Hospital, Tianjin, Hebei 300052, P.R. China
Published online on: April 24, 2018 https://doi.org/10.3892/mmr.2018.8925
Pages: 8039-8046
Copyright: © Lei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Neuroprotective strategies using diazoxide (DZX) have been demonstrated to limit ischemia/reperfusion (I/R)‑induced injury and cell apoptosis. In type 2 diabetes mellitus, DZX has been reported to improve β‑cell function and reduce their apoptosis, through suppressing endoplasmic reticulum (ER) stress. However, the effects of DZX on ER stress during I/R‑induced neuronal apoptosis in the hippocampus remains to be elucidated. In the present study, pretreatment of hippocampal neurons with DZX was revealed to inhibit oxygen‑glucose deprivation (OGD)‑stimulated apoptosis in vitro and to alleviate I/R‑induced hippocampal injury and behavioral deficits in rats in vivo. Furthermore, OGD and I/R were demonstrated to induce ER stress via upregulating the expression of ER stress‑associated proteins, including C/EBP homologous protein, 78 kDa glucose‑regulated protein and caspase‑12, whereas the exogenous administration of DZX effectively downregulated ER stress‑associated protein expression following OGD and I/R. In addition, DZX was revealed to significantly increase the protein expression of B‑cell lymphoma (Bcl)‑2 and suppress the expression of caspase‑3 and Bcl‑2‑associated X protein. These findings suggested that DZX may protect cells against apoptosis via regulating the expression of ER stress‑associated proteins in vitro and in vivo, thus enhancing the survival of hippocampal cells. The present results suggested a novel mechanism that may underlie the protective effect of DZX administration in the central nervous system.

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1	Cohn JN, Bristow MR, Chien KR, Colucci WS, Frazier OH, Leinwand LA, Lorell BH, Moss AJ, Sonnenblick EH, Walsh RA, et al: Report of the national heart, lung, and blood institute special emphasis panel on heart failure research. Circulation. 95:766–770. 1997. View Article : Google Scholar : PubMed/NCBI
2	Iadecola C: The pathobiology of vascular dementia. Neuron. 80:844–866. 2013. View Article : Google Scholar : PubMed/NCBI
3	Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, et al: ‘Ischemic tolerance’ phenomenon found in the brain. Brain Res. 528:21–24. 1990. View Article : Google Scholar : PubMed/NCBI
4	Dirnagl U, Simon RP and Hallenbeck JM: Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26:248–254. 2003. View Article : Google Scholar : PubMed/NCBI
5	Liu D, Lu C, Wan R, Auyeung WW and Mattson MP: Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release. J Cereb Blood Flow Metab. 22:431–443. 2002. View Article : Google Scholar : PubMed/NCBI
6	Shimizu K, Lacza Z, Rajapakse N, Horiguchi T, Snipes J and Busija DW: MitoK(ATP) opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat. Am J Physiol Heart Circ Physiol. 283:H1005–H1011. 2002. View Article : Google Scholar : PubMed/NCBI
7	Hausenloy DJ, Yellon DM, Mani-Babu S and Duchen MR: Preconditioning protects by inhibiting the mitochondrial permeability transition. Am J Physiol Heart Circ Physiol. 287:H841–H849. 2004. View Article : Google Scholar : PubMed/NCBI
8	Wu L, Shen F, Lin L, Zhang X, Bruce IC and Xia Q: The neuroprotection conferred by activating the mitochondrial ATP-sensitive K+ channel is mediated by inhibiting the mitochondrial permeability transition pore. Neurosci Lett. 402:184–189. 2006. View Article : Google Scholar : PubMed/NCBI
9	Busija DW, Katakam P, Rajapakse NC, Kis B, Grover G, Domoki F and Bari F: Effects of ATP-sensitive potassium channel activators diazoxide and BMS-191095 on membrane potential and reactive oxygen species production in isolated piglet mitochondria. Brain Res Bull. 66:85–90. 2005. View Article : Google Scholar : PubMed/NCBI
10	He X, Mo X, Gu H, Chen F, Gu Q, Peng W, Qi J, Shen L, Sun J, Zhang R and Kj Y: Neuroprotective effect of diazoxide on brain injury induced by cerebral ischemia/reperfusion during deep hypothermia. J Neurol Sci. 268:18–27. 2008. View Article : Google Scholar : PubMed/NCBI
11	Wang L, Zhu QL, Wang GZ, Deng TZ, Chen R, Liu MH and Wang SW: The protective roles of mitochondrial ATP-sensitive potassium channels during hypoxia-ischemia-reperfusion in brain. Neurosci Lett. 491:63–67. 2011. View Article : Google Scholar : PubMed/NCBI
12	Kaufman RJ: Orchestrating the unfolded protein response in health and disease. J Clin Invest. 110:1389–1398. 2002. View Article : Google Scholar : PubMed/NCBI
13	Schröder M and Kaufman RJ: The mammalian unfolded protein response. Annu Rev Biochem. 74:739–789. 2005. View Article : Google Scholar : PubMed/NCBI
14	Szegezdi E, Logue SE, Gorman AM and Samali A: Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7:880–885. 2006. View Article : Google Scholar : PubMed/NCBI
15	Sargsyan E, Ortsäter H, Thorn K and Bergsten P: Diazoxide-induced beta-cell rest reduces endoplasmic reticulum stress in lipotoxic beta-cells. J Endocrinol. 199:41–50. 2008. View Article : Google Scholar : PubMed/NCBI
16	Kirino T and Sano K: Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol. 62:201–208. 1984. View Article : Google Scholar : PubMed/NCBI
17	Horn M and Schlote W: Delayed neuronal death and delayed neuronal recovery in the human brain following global ischemia. Acta Neuropathol. 85:79–87. 1992. View Article : Google Scholar : PubMed/NCBI
18	Ghosh A, Sarkar S, Mandal AK and Das N: Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats. PLoS One. 8:e577352013. View Article : Google Scholar : PubMed/NCBI
19	Han L, Xu C, Jiang C, Li H, Zhang W, Zhao Y, Zhang L, Zhang Y, Zhao W and Yang B: Effects of polyamines on apoptosis induced by simulated ischemia/reperfusion injury in cultured neonatal rat cardiomyocytes. Cell Biol Int. 31:1345–1352. 2007. View Article : Google Scholar : PubMed/NCBI
20	Girard S, Brough D, Lopez-Castejon G, Giles J, Rothwell NJ and Allan SM: Microglia and macrophages differentially modulate cell death after brain injury caused by oxygen-glucose deprivation in organotypic brain slices. Glia. 61:813–824. 2013. View Article : Google Scholar : PubMed/NCBI
21	Oketani N, Kakei M, Ichinari K, Okamura M, Miyamura A, Nakazaki M, Ito S and Tei C: Regulation of K(ATP) channels by P(2Y) purinoceptors coupled to PIP(2) metabolism in guinea pig ventricular cells. Am J Physiol Heart Circ Physiol. 282:H757–H765. 2002. View Article : Google Scholar : PubMed/NCBI
22	Nakka VP, Gusain A and Raghubir R: Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats. Neurotox Res. 17:189–202. 2010. View Article : Google Scholar : PubMed/NCBI
23	Li Y, Chen J, Wang L, Lu M and Chopp M: Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology. 56:1666–1672. 2001. View Article : Google Scholar : PubMed/NCBI
24	Verma R, Harris NM, Friedler BD, Crapser J, Patel AR, Venna V and McCullough LD: Reversal of the detrimental effects of post-stroke social isolation by pair-housing is mediated by activation of BDNF-MAPK/ERK in aged mice. Sci Rep. 6:251762016. View Article : Google Scholar : PubMed/NCBI
25	Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA and Yuan J: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 403:98–103. 2000. View Article : Google Scholar : PubMed/NCBI
26	Hitomi J, Katayama T, Taniguchi M, Honda A, Imaizumi K and Tohyama M: Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neurosci Lett. 357:127–130. 2004. View Article : Google Scholar : PubMed/NCBI
27	Kondo F, Kondo Y, Makino H and Ogawa N: Delayed neuronal death in hippocampal CA1 pyramidal neurons after forebrain ischemia in hyperglycemic gerbils: Amelioration by indomethacin. Brain Res. 853:93–98. 2000. View Article : Google Scholar : PubMed/NCBI
28	Zarch AV, Toroudi HP, Soleimani M, Bakhtiarian A, Katebi M and Djahanguiri B: Neuroprotective effects of diazoxide and its antagonism by glibenclamide in pyramidal neurons of rat hippocampus subjected to ischemia-reperfusion-induced injury. Int J Neurosci. 119:1346–1361. 2009. View Article : Google Scholar : PubMed/NCBI
29	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–190. 2011. View Article : Google Scholar : PubMed/NCBI
30	Lakshmanan AP, Thandavarayan RA, Palaniyandi SS, Sari FR, Meilei H, Giridharan VV, Soetikno V, Suzuki K, Kodama M and Watanabe K: Modulation of AT-1R/CHOP-JNK-Caspase12 pathway by olmesartan treatment attenuates ER stress-induced renal apoptosis in streptozotocin-induced diabetic mice. Eur J Pharm Sci. 44:627–634. 2011.PubMed/NCBI
31	Seimon TA, Obstfeld A, Moore KJ, Golenbock DT and Tabas I: Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages. Proc Natl Acad Sci USA. 103:19794–19799. 2006. View Article : Google Scholar : PubMed/NCBI
32	Timmins JM, Ozcan L, Seimon TA, Li G, Malagelada C, Backs J, Backs T, Bassel-Duby R, Olson EN and Anderson ME: Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J Clin Invest. 119:2925–2941. 2009. View Article : Google Scholar : PubMed/NCBI
33	Li G, Scull C, Ozcan L and Tabas I: NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J Cell Biol. 191:1113–1125. 2010. View Article : Google Scholar : PubMed/NCBI
34	Palomeque J, Rueda OV, Sapia L, Valverde CA, Salas M, Petroff MV and Mattiazzi A: Angiotensin II-induced oxidative stress resets the Ca2+ dependence of Ca2+-calmodulin protein kinase II and promotes a death pathway conserved across different species. Circ Res. 105:1204–1212. 2009. View Article : Google Scholar : PubMed/NCBI
35	Murata M, Akao M, O'Rourke B and Marbán E: Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca(2+) overload during simulated ischemia and reperfusion: Possible mechanism of cardioprotection. Circ Res. 89:891–898. 2001. View Article : Google Scholar : PubMed/NCBI