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Antagonistic effects of IL-17 and Astragaloside IV on cortical neurogenesis and cognitive behavior after stroke in adult mice through Akt/GSK-3β pathway.
Cell Death Discovery ( IF 6.1 ) Pub Date : 2020-08-10 , DOI: 10.1038/s41420-020-00298-8
Li Sun 1 , Ruili Han 1 , Fei Guo 1 , Hai Chen 1 , Wen Wang 2 , Zhiyang Chen 1 , Wei Liu 1 , Xude Sun 1 , Changjun Gao 1
Affiliation  

We aimed to investigate the exact effect of IL-17 on regulating neural stem cells (NSCs) stemness and adult neurogenesis in ischemic cortex after stroke, how Astragaloside IV(As-IV) regulated IL-17 expression and the underlying mechanism. Photochemical brain ischemia model was established and IL-17 protein expression was observed at different time after stroke in WT mice. At 3 days after stroke, when IL-17 expression peaked, IL-17 knock out (KO) mice were used to observe cell proliferation and neurogenesis in ischemic cortex. Then, As-IV was administered intravenously to assess cell apoptosis, proliferation, neurogenesis, and cognitive deficits by immunochemistry staining, western blots, and animal behavior tests in WT mice. Furthermore, IL-17 KO mice and As-IV were used simultaneously to evaluate the mechanism of cell apoptosis and proliferation after stroke in vivo. Besides, in vitro, As-IV and recombinant mouse IL-17A was administered, respectively, into NSCs culture, and then their diameters, viable cell proliferation and pathway relevant protein was assessed. The results showed knocking out IL-17 contributed to regulating PI3K/Akt pathway, promoting NSCs proliferation, and neurogenesis after ischemic stroke. Moreover, As-IV treatment helped inhibit neural apoptosis, promote the neurogenesis and eventually relieve mice anxiety after stroke. Unsurprisingly, IL-17 protein expression could be downregulated by As-IV in vivo and in vitro and they exerted antagonistic effect on neurogenesis by regulating Akt/GSK-3β pathway, with significant regulation for apoptosis. In conclusion, IL-17 exerts negative effect on promoting NSCs proliferation, neurogenesis and cognitive deficits after ischemic stroke, which could be reversed by As-IV.



中文翻译:

IL-17 和黄芪甲苷 IV 通过 Akt/GSK-3β 途径对成年小鼠中风后皮质神经发生和认知行为的拮抗作用。

我们的目的是研究IL-17对调节脑卒中后缺血皮质神经干细胞(NSC)干性和成体神经发生的确切作用,黄芪甲苷IV(As-IV)如何调节IL-17表达及其潜在机制。建立光化学脑缺血模型,观察WT小鼠脑卒中后不同时间IL-17蛋白表达。中风后3天,当IL-17表达达到峰值时,使用IL-17敲除(KO)小鼠观察缺血皮质中的细胞增殖和神经发生。然后,静脉注射 As-IV,通过免疫化学染色、蛋白质印迹和动物行为测试来评估 WT 小鼠的细胞凋亡、增殖、神经发生和认知缺陷。此外,同时使用IL-17 KO小鼠和As-IV来评估体内中风后细胞凋亡和增殖的机制。此外,在体外,将As-IV和重组小鼠IL-17A分别施用到NSCs培养物中,然后评估它们的直径、活细胞增殖和通路相关蛋白。结果显示,敲除IL-17有助于调节PI3K/Akt通路,促进NSCs增殖和缺血性中风后的神经发生。此外,As-IV治疗有助于抑制神经细胞凋亡,促进神经发生,最终缓解小鼠中风后的焦虑。不出所料,As-IV 在体内和体外均可下调 IL-17 蛋白表达,并通过调节 Akt/GSK-3β 通路对神经发生发挥拮抗作用,并对细胞凋亡具有显着调节作用。总之,IL-17 对促进缺血性中风后 NSC 增殖、神经发生和认知缺陷产生负面影响,而 As-IV 可以逆转这种负面影响。

更新日期:2020-08-11
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