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.
Highlights
Stroke has become the second leading cause of death worldwide and seriously affects public health
During the acute phase of cerebral ischemia, blood vessel blockade leads to calcium overload and energy depletion in nerve cells, which can induce the accumulation of reactive oxygen species (ROS) and subsequent brain injury after the Oxidative Medicine and Cellular Longevity resupply of oxygen and nutrients
We examined the neuroprotective role of γGC in the HT22 neuronal cell line and primary cortical neurons exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) injury and in mice subjected to Middle cerebral artery occlusion (MCAO)-induced ischemia-reperfusion injury
Summary
Stroke has become the second leading cause of death worldwide and seriously affects public health. Attenuating excessive ROS production can reduce the apoptosis of penumbra neurons and protect against ischemic brain injury. Oral administration of exogenous GSH exerts a protective effect on rats with ischemic stroke [15]. Animal model studies have shown that exogenous GSH and NAC have therapeutic effects on cerebral ischemia, these agents are still far from ideal for clinical applications. Γ-GC has been shown to inhibit oxidative injury in endothelial cells [24] Despite these findings, much less is known about the effects of γ-GC on ROS-mediated neuronal apoptosis after ischemic stroke. We conducted transcriptomics analysis to explore the potential molecular and cellular pathways underlying these protective effects of γ-GC These results provide a novel therapeutic strategy for treating cerebral ischemia
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