GABAB Receptor-Mediated PI3K/Akt Signaling Pathway Alleviates Oxidative Stress and Neuronal Cell Injury in a Rat Model of Alzheimer's Disease.

JOURNAL OF ALZHEIMERS DISEASE(2020)

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摘要
Background: Oxidative stress has been implicated in Alzheimer's disease (AD) as a common pathway underlying neuronal damage causing huge impacts on cognitive functions in the AD process. Objective: Reduction and remodeling of gamma-aminobutyric acid (GABA) signaling in AD may promote neuronal survival by regulating PI3K/Akt axis. Moreover, its activation exerts beneficial effects on AD by alleviating the neuronal oxidative stress injury. Considering these facts, we hypothesized the GABA(B) receptor as a novel therapeutic target for AD. Methods: To evaluate this hypothesis, a rat AD model was established by intraperitoneal injection of the GABA(B) receptor agonist (baclofen), PI3K/Akt signaling pathway agonist (740 Y-P), and antagonist (LY294002), respectively. The effects of GABA(B) activation on spatial memory and learning ability in the AD rats were measured by Morris water maze. Whereas the effects of GABA(B) and PI3K/Akt signaling pathway on apoptosis and oxidative stress injury were determined in vivo and in vitro using primary neuronal cultures. Results: We found that GABA(B) receptor activation restored spatial memory and learning ability of AD rats and suppressed the neuronal apoptosis and hippocampal atrophy by activating the PI3K/Akt signaling pathway. Additionally, GABA(B) receptor activation reduced the oxidative stress injury by lowering the MDA levels and increased the SOD, GSH-Px, and CAT levels via activation of the PI3K/Akt signaling pathway. Conclusion: Taken together, our results suggest that GABA(B) receptor activation repressed the oxidative stress injury implicated in neurons in AD rats via PI3K/Akt signaling pathway activation which may suggest a potential new therapeutic target for AD.
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关键词
Alzheimer's disease,GABA(B) receptor,oxidative stress injury,PI3K/Akt signaling pathway
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