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 γ-aminobutyric acid (GABA) signaling in AD may promote neuronal survival byregulating PI3K/Akt axis. Moreover, its activation exerts beneficial effects on AD by alleviating the neuronal oxidative stress injury. Considering these facts, we hypothesized the GABAB receptor as a novel therapeutic target for AD. Methods:To evaluate this hypothesis, a rat AD model was established by intraperitoneal injection of the GABAB receptor agonist (baclofen), PI3K/Akt signaling pathway agonist (740 Y-P), and antagonist (LY294002), respectively. The effects of GABAB activation on spatial memory and learning ability in the AD rats were measured by Morris water maze. Whereas the effects of GABAB 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 GABAB 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, GABAB 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 GABAB 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.

中文翻译：

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GABA B受体介导的PI3K / Akt信号通路减轻了阿尔茨海默氏病大鼠模型的氧化应激和神经元细胞损伤。

背景：氧化应激与阿尔茨海默氏病（AD）有关，是神经元受损的常见途径，会对AD进程的认知功能产生巨大影响。目的：减少和重塑AD中γ-氨基丁酸（GABA）信号传导可能通过调节PI3K / Akt轴来促进神经元存活。此外，其活化通过减轻神经元氧化应激损伤而对AD产生有益作用。考虑到这些事实，我们假设GABA B受体是AD的新型治疗靶标。方法：为了评估该假设，分别通过腹膜内注射GABAB受体激动剂（baclofen），PI3K / Akt信号通路激动剂（740 YP）和拮抗剂（LY294002）建立了大鼠AD模型。用莫里斯水迷宫测量了GABA B活化对AD大鼠空间记忆和学习能力的影响。然而，使用原代神经元培养物在体内和体外确定了GABA B和PI3K / Akt信号通路对细胞凋亡和氧化应激损伤的影响。结果：我们发现，GABA B受体的激活通过激活PI3K / Akt信号通路来恢复AD大鼠的空间记忆和学习能力，并抑制神经元凋亡和海马萎缩。此外，GABA B受体的激活通过降低MDA的水平降低了氧化应激损伤，并通过激活PI3K / Akt信号通路提高了SOD，GSH-Px和CAT的水平。结论：一起，