Cerebral ischemic/reperfusion injury (CIRI) is a key factor affecting the prognosis of ischemic stroke (IS), the leading disease in global disability and fatality rates. Recent studies have shown that endoplasmic reticulum stress (ERS) may be a potential target against CIRI and leptin, a peptide hormone, has neuroprotective activity to mitigate CIRI. In present study, an in vitro CIRI model was induced in primary cortical neurons by oxygen-glucose deprivation and reoxygenation (OGD/R) after

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... treatment with LY294002 (10 umol/L) or (and) leptin (0.4 mg/L), and then cell viability, neuronal morphology as well as endoplasmic reticulum dysfunction were evaluated. An in vivo CIRI model was established in rats by middle cerebral artery occlusion and reperfusion (MCAO/R) after injecting LY294002 (10 µmol/L) or (and) leptin (1 mg/kg), and studies for neurological function, infarct volume, cerebral pathological changes, the expression of ERS-related proteins along with cell apoptosis. In vitro, leptin treatment improved cell survival rate, ameliorated pathological morphology of neurons and alleviated OGD/R-induced ERS. In vivo, administration of leptin showed a significant reduction in infarct volume, neurological deficits scores and neuronal apoptosis as well as pathological alterations. In addition, leptin suppressed MCAO/R-induced ERS and have anti-apoptotic potential by inhibiting the ERS-related death and caspase 3 activation. It also regulates anti-apoptotic, Bcl-2 and pro- apoptotic, Bax proteins in cortex region. Furthermore, the inhibitory of leptin on ERS was significantly weakened by the specific PI3K inhibitor LY294002. Our findings elucidate the neuroprotective mechanism of leptin, and reinforce its role as a potential agent for treatment of CIRI.