GCN2 suppression attenuates cerebral ischemia in mice by reducing apoptosis and endoplasmic reticulum (ER) stress through the blockage of FoxO3a-regulated ROS production.

Abstract

Ischemic stroke is one of the leading causes of morbidity and mortality among human worldwide. Unfortunately, cerebral I/R still lacks effective therapeutic targets and strategies. In the study, we found that general control nonderepressible 2 (GCN2) expression was increased following ischemia in the ischemic penumbra in\xa0vivo and in\xa0vitro. GCN2 suppression using its significant inhibitor, GCN2iB, exhibited a protective role in cerebral I/R injury in mice, as evidenced by the improved neurological deficits and function. GCN2 inhibition with either GCN2iB or genetic knockdown led to significant reduction of pro-apoptotic protein expression, endoplasmic reticulum stress (ERS)-related protein and oxidative stress both in I/R-induced cerebral injury and oxygen-glucose deprivation and reoxygenation (OGD/R) stimulation in N2a\u202fcells. OGD/R-triggered apoptosis and ERS were significantly depended on oxidative stress in\xa0vitro. In addition, Forkhead box O 3a (FoxO3a), involved in the reactive oxygen species (ROS) production, was increased during OGD/R stimulation-regulated apoptosis and ERS, which could be abrogated by GCN2 suppression. Consistently, FoxO3a-regulated generation of ROS was markedly ameliorated upon GCN2 suppression with GCN2iB. Thereby, our findings indicated that GCN2 suppression alleviated apoptosis and ERS in cerebral ischemia through reducing FoxO3a-dependent ROS production, illustrating that GCN2 could be a promising target for the therapeutic interventions in cerebral ischemic stroke.