Aims

Neuronal apoptosis acts as the pivotal pathogenesis of cerebral ischemia/reperfusion (I/R) injury after ischemic stroke. PAQR3 (progestin and adipoQ receptor family member 3) is a crucial player who participates in the regulation of cell death. We aim to explore the specific function and the underlying mechanism of PAQR3 in cerebral I/R induced neuronal injury.

Main methods

We established a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model and rat adrenal pheochromocytoma (PC12) cell oxygen-glucose deprivation/reperfusion (OGD/R) model to detect the expression and of PAQR3 after I/R treatment in vivo and in vitro. We used lentivirus to knockdown PAQR3 and investigated the function of PAQR3 in I/R induced neuronal apoptosis.

Key findings

PAQR3 expression is markedly increased in the ischemic hemisphere of C57BL/6 mice and PC12 cells after I/R stimulation. Knockdown PAQR3 can attenuate neuronal apoptosis induced by I/R in PC12 cells and exerts neuroprotective effects. PAQR3 deficiency can significantly raise cell viability and suppress LDH leakage under I/R treatment. Silencing PAQR3 attenuates neuronal apoptosis remarkably with fewer TUNEL-positive cells and lower apoptosis rate under I/R treatment. Mechanistically, knockdown of PAQR3 can inhibit the apoptosis pathway through inducing anti-apoptotic proteins and inhibiting pro-apoptotic proteins. Besides, PI3K/AKT signaling suppression with LY294002 abolished the neuroprotective functions induced by silencing PAQR3.

Significance

Our results elucidate that silencing PAQR3 can protect PC12 from OGD/R injury via activating PI3K/AKT pathway. And therefore, provide a novel therapeutic target for the prevention of cerebral I/R injury.

中文翻译：

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沉默PAQR3通过激活PC12细胞中的PI3K / AKT信号传导来防止氧葡萄糖剥夺/再灌注诱导的神经元凋亡

目的

神经元凋亡是缺血性中风后脑缺血/再灌注（I / R）损伤的关键发病机制。PAQR3（孕激素和adipoQ受体家族成员3）是参与细胞死亡调控的关键参与者。我们旨在探讨PAQR3在脑I / R诱导的神经元损伤中的特定功能及其潜在机制。

主要方法

我们建立了小鼠大脑中动脉闭塞/再灌注（MCAO / R）模型和大鼠肾上腺嗜铬细胞瘤（PC12）细胞氧葡萄糖剥夺/再灌注（OGD / R）模型，以检测体内I / R治疗后的表达和PAQR3和体外。我们使用慢病毒来敲低PAQR3，并研究了PAQR3在I / R诱导的神经元凋亡中的功能。

主要发现

I / R刺激后，在C57BL / 6小鼠和PC12细胞的缺血半球中，PAQR3表达显着增加。敲低PAQR3可以减弱I / R诱导PC12细胞中的神经元凋亡，并发挥神经保护作用。PAQR3缺乏症可在I / R处理下显着提高细胞活力并抑制LDH泄漏。在I / R处理下，沉默PAQR3可显着减弱TUNEL阳性细胞并降低凋亡率，从而显着减轻神经元凋亡。从机理上讲，敲低PAQR3可以通过诱导抗凋亡蛋白和抑制促凋亡蛋白来抑制细胞凋亡途径。此外，用LY294002抑制PI3K / AKT信号消除了沉默PAQR3诱导的神经保护功能。

意义

我们的结果表明沉默PAQR3可以通过激活PI3K / AKT途径保护PC12免受OGD / R损伤。因此，提供了一种预防脑I / R损伤的新型治疗靶标。