Neuroprotective effects of irisin against cerebral ischemia/ reperfusion injury via Notch signaling pathway
Neuroprotective effects of irisin against cerebral ischemia/ reperfusion injury via Notch signaling pathway
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DOI：
10.1016/j.biopha.2019.109452
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发表时间：
2019-12-01
影响因子：
7.5
通讯作者：
Wu, Huisheng
中科院分区：
文献类型：
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作者：
Jin, Zhao;Guo, Peipei;Wu, Huisheng
淫羊藿素是一种由112个氨基酸组成的多肽，在小鼠和人类中被运动诱导，被认为与缺血性中风患者的短期预后有关。本研究对淫羊藿素的体内外神经保护作用进行了评价，并对其作用机制进行了初步探讨。采用小鼠双侧颈总动脉结扎20min再灌流24 h和HT22细胞缺氧缺糖再灌流的方法建立全脑缺血/再灌注模型。神经功能评分后处死小鼠。取脑组织行HE染色和脑含水量(BWC)检测。用原位末端标记法和流式细胞仪检测神经细胞凋亡率。逆转录-聚合酶链式反应检测肿瘤坏死因子-α和白介素1-β的mRNA表达。免疫荧光双重染色和Western印迹法检测Notch胞内区(NICD)，免疫印迹法检测Notch1、Hes 1蛋白表达。观察到淫羊藿素能减轻小鼠全脑I/R损伤后的形态损害，改善神经功能。在体内和体外，淫羊藿素均能减少海马神经元的凋亡率。此外，淫羊藿体内外均可下调IL-1β、TNF-α的表达，上调NICD、Notch1、Hes-1的表达。应用γ-分泌酶抑制剂DAPT后，所有的形态、神经和生化改变均被逆转。综上所述，这些结果提示淫羊藿素可以调节Notch信号通路，从而减轻短暂性全脑I/R损伤。
Irisin, a 112-amino acid peptide induced with exercise in mice and human is thought to have correlation with the short-term outcomes of patients in ischemic stroke. In the present study, the neuroprotective effects of irisin were evaluated in vivo and in vitro and its underlying mechanism was also explored. The global cerebral ischemia/ reperfusion (I/R) model was established by bilateral common carotid artery occlusion for 20 min and reperfusion for 24 h in mice and oxygen-glucose deprivation/reperfusion in HT22 cells. Neurological function was scored and then the mice were sacrificed. The brains were harvested for HE staining and detection of brain water content (BWC). The percentage of neuronal apoptosis was evaluated by TUNEL and flow cytometry analysis. The mRNA expression of TNF-alpha and IL-1 beta was detected by RT-PCR analysis. The Notch intracellular domain (NICD) was detected by double immunofluorescence staining and western blot, and the protein expression of Notch1 and Hes 1 was detected by western blot. It was observed that irisin could alleviate morphological damage and improve neurological function after global cerebral I/R injury in mice. The apoptosis of hippocampal neurons reduced in the presence of irisin in vivo and in vitro. Additionally irisin could downregulate the expression of IL-1 beta and TNF-alpha and upregulate the expression of NICD, Notch1 and Hes 1 in vitro and in vivo. After the application of gamma-secretase inhibitor DAPT, all the morphological, neurological and biochemical changes were reversed. Taken together, these results suggest that irisin could regulate the Notch signaling pathway that leads to the alleviation of transient global cerebral I/R injury.