Kisspeptin-54 attenuates oxidative stress and neuronal apoptosis in early brain injury after subarachnoid hemorrhage in rats via GPR54/ARRB2/AKT/GSK3β signaling pathway.
Kisspeptin-54 attenuates oxidative stress and neuronal apoptosis in early brain injury after subarachnoid hemorrhage in rats via GPR54/ARRB2/AKT/GSK3β signaling pathway.
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DOI：
10.1016/j.freeradbiomed.2021.05.012
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发表时间：
2021-08-01
影响因子：
7.4
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Huang Y;Guo Y;Huang L;Fang Y;Li D;Liu R;Lu Q;Ren R;Tang L;Lian L;Hu Y;Tang J;Chen G;Zhang JH
氧化应激诱导的神经元凋亡在蛛网膜下腔出血（SAH）后的早期脑损伤（EBI）中起着至关重要的作用。据报道 Kisspeptin 是一种抗氧化剂，可通过 G 蛋白偶联受体 54 (GPR54) 减少氧化应激诱导的神经细胞死亡。本研究的目的是确定 Kisspeptin/GRP54 信号通路对 SAH 后 EBI 的神经保护作用。使用292只Sprague Dawley雄性大鼠，通过血管内穿孔诱导SAH。鼻内递送外源性 Kisspeptin 54 (KP54)。脑室内注射内源性 KISS1 的小干扰核糖核酸 (siRNA)、选择性 GPR54 拮抗剂 Kisspeptin 234 或 ARRB2（GPR54 的功能接头）的 β-arrestin 2 siRNA。 SAH 后评估包括神经行为测试、SAH 分级、蛋白质印迹、免疫荧光、Fluoro-Jade C、TUNEL 和尼氏染色。结果显示，内源性 KISS1 敲低会加重 SAH 后 24 小时的神经功能缺损、脑氧化应激和神经元凋亡，而外源性 KP54 (1.0 nmol/kg) 治疗则会减轻。 KP54的益处持续到SAH后28天，显着改善SAH大鼠的认知功能。 GPR54 阻断或 ARRB2 敲除抵消了 KP54 对 SAH 大鼠的神经保护作用。总之，我们的结果表明，在大鼠蛛网膜下腔出血后，给予 KP54 通过 GPR54/ARRB2/AKT/GSK3β 信号通路减轻氧化应激、神经元凋亡和神经行为损伤。因此，KP54可能为SAH患者提供有效的治疗策略。
Oxidative stress-induced neuron apoptosis plays a crucial role in the early brain injury (EBI) after subarachnoid hemorrhage (SAH). Kisspeptin has been reported as antioxidant to reduce oxidative stress-induced neuronal cell death through G protein-coupled receptor 54 (GPR54). The goal of this study was to determine the neuroprotection of the Kisspeptin/GRP54 signaling pathway against EBI after SAH. Two hundred and ninety-two Sprague Dawley male rats were used and SAH was induced by the endovascular perforation. Exogenous Kisspeptin 54 (KP54) was delivered intranasally. Small interfering ribonucleic acid (siRNA) for endogenous KISS1, a selective GPR54 antagonist kisspeptin 234, or β-arrestin 2 siRNA for ARRB2 (a functional adaptor of GPR54) were administered intracerebroventricularly. Post-SAH evaluations included neurobehavioral tests, SAH grade, Western blot, immunofluorescence, Fluoro-Jade C, TUNEL, and Nissl staining. The results showed that endogenous KISS1 knockdown aggravated but exogenous KP54 (1.0 nmol/kg) treatment attenuated neurological deficits, brain oxidative stress, and neuronal apoptosis at 24 h after SAH. The benefits of KP54 persisted to 28 days after SAH, which significantly improved cognitive function in SAH rats. The GPR54 blockade or the ARRB2 knockout offset the neuroprotective effects of KP54 in SAH rats. In conclusion, our results suggested that administration of KP54 attenuated oxidative stress, neuronal apoptosis and neurobehavioral impairments through GPR54/ARRB2/AKT/GSK3β signaling pathway after SAH in rat. Thus, KP54 may provide an effective treatment strategy for SAH patients.
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