γ‐Glutamylcysteine Alleviates Ischemic Stroke‐Induced Neuronal Apoptosis by Inhibiting ROS‐Mediated Endoplasmic Reticulum Stress

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 γ-glutamylcysteine (γ-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 γ-GC treatment mitigated oxidative stress, as indicated by upregulated GSH and decreased ROS levels. In addition, γ-GC attenuated ischemia/reperfusion-induced neuronal apoptosis and brain injury in vivo and in vitro. Furthermore, transcriptomics approaches and subsequent validation studies revealed that γ-GC attenuated penumbra neuronal apoptosis by inhibiting the activation of protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1α (IRE1α) 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 γ-GC attenuates ischemia-induced neuronal apoptosis by suppressing ROS-mediated ER stress. γ-GC may be a promising therapeutic agent for ischemic stroke.

Deltamethrin induces apoptosis in cerebrum neurons of quail via promoting endoplasmic reticulum stress and mitochondrial dysfunction

“…ER stress, as a protective stress response in eukaryotic cells, can be activated by the imbalanced homeostasis 9 . Once ER stress arises, excessive improperly folded proteins accumulate in the ER lumen 10 . The unfolded protein response (UPR) then occurs, which is sensed and activated by three transmembrane proteins, activating transcription factor 6 (ATF6), inositol requiring enzyme (IRE), and protein kinase RNA (PKR)‐like ER kinase (PERK) 11 .…”

“…9 Once ER stress arises, excessive improperly folded proteins accumulate in the ER lumen. 10 The unfolded protein response (UPR) then occurs, which is sensed and activated by three transmembrane proteins, activating transcription factor 6 (ATF6), inositol requiring enzyme (IRE), and protein kinase RNA (PKR)-like ER kinase (PERK). 11 URP plays a crucial role in the restoration of ER homeostasis.…”

Integrative Analyses of Biomarkers Associated with Endoplasmic Reticulum Stress in Ischemic Stroke

“…A previous study has revealed that the promotion of ERS via knockdown Hes1 induced vast neuronal apoptosis in a mouse model with middle cerebral artery occlusion (MCAO) [ 25 ]. In addition, Li et al reported that the inhibition of ERS signal pathway by γ -glutamylcysteine attenuated neuronal apoptosis in the ischemic brain of mice [ 28 ]. The aforementioned results support the idea that ERS may be a potential target in IS injury.…”

Amplifying the human body’s innate “rapid response” systems to inflammation and oxidative stress

“…In addition, consuming pre-formed glutathione is an inefficient way to raise cellular levels of glutathione since published clinical studies demonstrate that it may take weeks or months to impact cellular levels when elevated levels are most needed acutely. [31][32][33][34][35][36][37][38][39][40][41][42][43] concept should be considered and tested using this approach in conjunction with measuring blood biomarkers that reflect individual and pathway proteins that correspond to inflammation and oxidative stress.…”