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

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.