Leptin alleviates endoplasmic reticulum stress induced by cerebral ischemia/reperfusion injury via the PI3K/Akt signaling pathway

Abstract

Background: Cerebral ischemic/reperfusion injury (CIRI) is a key factor for the prognosis of ischemic stroke (IS). Recent studies have shown that endoplasmic reticulum stress (ERS) may be a target against CIRI and that leptin, a peptide hormone, has neuroprotective activity to mitigate CIRI. Methods: An in vitro CIRI model was induced in primary cortical neurons by oxygen-glucose deprivation and reoxygenation (OGD/R) after pretreatment with LY294002 (10 µmol/L) and/or leptin (0.4 mg/L), and cell viability, neuronal morphology and endoplasmic reticulum (ER) dysfunction were evaluated. An in vivo CIRI model was established in rats by middle cerebral artery occlusion and reperfusion (MCAO/R) after the injection of LY294002 (10 μmol/L) and/or leptin (1 mg/kg), and neurological function, infarct volume, cerebral pathological changes, the expression of ERS-related proteins and cell apoptosis were examined. Results: In vitro, leptin treatment improved the cell survival rate, ameliorated neuronal pathological morphology and alleviated ERS. In vivo, administration of leptin significantly reduced the infarct volume, neurological deficit scores and neuronal apoptosis. In addition, leptin suppressed MCAO/R-induced ERS and may decrease apoptosis by inhibiting ERS-related death and caspase 3 activation. It also regulated expression of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bax. Furthermore, the inhibitory effect of leptin on ERS was significantly decreased by the effective phosphatidylinositol 3-kinase inhibitor LY294002. Conclusions: These results confirm that ERS plays an important role in CIRI and that leptin can inhibit the activation of ERS through the PI3K/Akt pathway, thereby alleviating CIRI. These findings provide novel therapeutic targets for IS.

Obesity as a Limiting Factor for Remote Ischemic Postconditioning-Mediated Neuroprotection after Stroke

“… 24 Its administration in vivo resulted in a decrease in cerebral infarction, morphological damage and neuronal apoptosis, demonstrating that leptin reduces the secondary events of brain injury after ischemia. 25 The fat content and BMI may be other factors that influence RIPostC inefficacy. To the best of our knowledge, the present study was the first to investigate RIPostC-induced neuroprotection in obese animals.…”

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

“…The originally described central actions of leptin were mainly related to the regulation of food intake and energy homeostasis at the hypothalamic level [ 91 ]. Subsequently, it was reported that leptin is also involved in neurogenesis and has neuroprotective actions [ 92 ]. Thus, changes in its functionality may be related to alterations in the regulation of body weight, or different neurodegenerative processes.…”

Xingnaojing injection alleviates cerebral ischemia/reperfusion injury through regulating endoplasmic reticulum stress in Vivo and in Vitro

“…Nonetheless, in certain instances, reperfusion of cerebral blood flow not only fails to alleviate disease progression but also exacerbates damage to ischemic brain tissues, recognised as cerebral ischemia-reperfusion injury (CIRI) [ [5] , [6] , [7] ]. Neurological deficits in ischemic stroke are due to a series of complex pathological processes, of which CIRI is the core pathological link [ 8 ]. Thus, attenuating CIRI is essential for the management of acute IS.…”