Gamma-Glutamylcysteine Alleviates Ischemic Stroke-Induced Neuronal Apoptosis by Inhibiting ROS-Mediated Endoplasmic Reticulum Stress

Authors
H Li, S Xia, S Xu et al

Lab
Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China

Journal
Oxidative Medicine and Cellular Longevity

Abstract
Ischemic stroke is a severe and acute neurological disorder with limited therapeutic strategies currently available. Oxidative stress is one of the critical pathological factors in ischemia/reperfusion injury, and high levels of reactive oxygen species (ROS) may drive neuronal apoptosis. Rescuing neurons in the penumbra is a potential way to recover from ischemic stroke. Endogenous levels of the potent ROS quencher glutathione (GSH) decrease significantly after cerebral ischemia. Here, we aimed to investigate the neuroprotective effects of gamma-glutamylcysteine (gamma-GC), an immediate precursor of GSH, on neuronal apoptosis and brain injury during ischemic stroke. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice, neuronal cell lines, and primary neurons. Our data indicated that exogenous gamma-GC treatment mitigated oxidative stress, as indicated by upregulated GSH and decreased ROS levels. In addition, gamma-GC attenuated ischemia/reperfusion-induced neuronal apoptosis and brain injury in vivo and in vitro. Furthermore, transcriptomics approaches and subsequent validation studies revealed that gamma-GC attenuated penumbra neuronal apoptosis by inhibiting the activation of protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1_ (IRE1_) in the endoplasmic reticulum (ER) stress signaling pathway in OGD/R-treated cells and ischemic brain tissues. To the best of our knowledge, this study is the first to report that gamma-GC attenuates ischemia-induced neuronal apoptosis by suppressing ROS-mediated ER stress. Gamma-GC may be a promising therapeutic agent for ischemic stroke.

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)