The Activation of GABA[sub.A]R Alleviated Cerebral Ischemic Injury via the Suppression of Oxidative Stress, Autophagy, and Apoptosis Pathways.

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Authors: Jing Lan, Jiaqi Wang, Shujing Wang, Jia Wang, Sijuan Huang and Yazhou Wang
Date: Feb. 2024
From: Antioxidants(Vol. 13, Issue 2)
Publisher: MDPI AG
Document Type: Article
Length: 9,979 words

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Abstract :

Ischemic stroke is a devastating disease leading to neurologic impairment. Compounding the issue is the very limited array of available interventions. The activation of a γ-aminobutyric acid (GABA) type A receptor (GABA A R) has been reported to produce neuroprotective properties during cerebral ischemia, but its mechanism of action is not yet fully understood. Here, in a rat model of photochemically induced cerebral ischemia, we found that muscimol, a GABA A R agonist, modulated GABAergic signaling, ameliorated anxiety-like behaviors, and attenuated neuronal damage in rats suffering cerebral ischemia. Moreover, GABA A R activation improved brain antioxidant levels, reducing the accumulation of oxidative products, which was closely associated with the NO/NOS pathway. Notably, the inhibition of autophagy markedly relieved the neuronal insult caused by cerebral ischemia. We further established an oxygen–glucose deprivation (OGD)-induced PC12 cell injury model. Both in vivo and in vitro experiments demonstrated that GABA A R activation obviously suppressed autophagy by regulating the AMPK-mTOR pathway. Additionally, GABA A R activation inhibited apoptosis through inhibiting the Bax/Bcl-2 pathway. These data suggest that GABA A R activation exerts neuroprotective effects during cerebral ischemia through improving oxidative stress and inhibiting autophagy and apoptosis. Our findings indicate that GABA A R serves as a target for treating cerebral ischemia and highlight the GABA A R-mediated autophagy signaling pathway.

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Gale Document Number: GALE|A784035674