Hispidulin exhibits neuroprotective activities against cerebral ischemia reperfusion injury through suppressing NLRP3-mediated pyroptosis
Hispidulin exhibits neuroprotective activities against cerebral ischemia reperfusion injury through suppressing NLRP3-mediated pyroptosis
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DOI：
10.1016/j.lfs.2019.116599
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发表时间：
2019-09-01
期刊：
影响因子：
6.1
通讯作者：
Tang, Ming
中科院分区：
文献类型：
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作者：
An, Pengpeng;Xie, Jing;Tang, Ming
目的：缺血/再灌注（I/R）损伤是脑卒中后神经功能缺损的主要原因。我们前期的研究表明hispidulin对脑缺血再灌注损伤（IRI）具有神经保护作用。在这项研究中，我们进一步研究了参与pyroptosis在这neuroprotective function.Materials和方法：IRI是模拟在大鼠模型大脑中动脉闭塞（MCAO）手术，和动物进行了治疗与不同剂量的hispidulin。采用神经功能缺损评分（NFDS）、平衡木试验和肢体放置试验评价大鼠的神经功能。IRI后72 h测定脑梗死体积和脑含水量。采用尼氏染色法和TUNEL法分别检测缺血区神经细胞存活和凋亡情况。适当时，通过qRT-PCR、蛋白质印迹和ELISA测定焦亡标志物的相对表达。使用OGD/R程序在体外在原代脑星形胶质细胞中模拟IRI。AMPK α分别用siRNA和化合物C进行遗传或药理学阻断。结果：Hispidulin能明显改善IRI大鼠的神经症状，并能缩小梗死面积和减轻脑水肿。Hispidulin通过调节AMPK/GSK 3 β信号通路抑制NLRP 3介导的细胞凋亡，在体内和体外发挥神经保护作用。结论：Hispidulin是一种具有临床应用潜力的神经保护剂，可对抗IR诱导的神经损伤。
Aim: Ischemia/reperfusion (I/R) injury is the major cause of neurological deficit following stroke. Our previous study showed neuroprotective effects of hispidulin against cerebral ischemia reperfusion injury (IRI). In this study, we further examined the involvement of pyroptosis in this neuroprotective function.Materials and methods: IRI was simulated in a rat model by middle cerebral artery occlusion (MCAO) surgery, and the animals were treated with different doses of hispidulin. The neurological function of the rats was evaluated by the neural function defect score (NFDS), balance beam test and limb placement test. The infarct volume and brain water content were measured 72 h following IRI. Neuronal cell survival and pyroptosis in the ischemic cortex were respectively detected by Nissl staining and TUNEL assay. The relative expression of pyroptosis markers was determined by qRT-PCR, Western blotting and ELISA as appropriate. IRI was simulated in vitro in primary cerebral astrocytes using the OGD/R procedure. AMPK alpha was blocked genetically or pharma-cologically using siRNA and compound C respectively. CCK-8 and LDH release assays were performed using suitable kits.Results: Hispidulin improved the neurological symptoms of the rats after IRI, in addition to decreasing the infarct size and brain edema. Mechanistically, hispidulin exerted its neuroprotective effects in vivo and in vitro by suppressing NLRP3-mediated pyroptosis by modulating the AMPK/GSK3 beta signaling pathway.Conclusion: Hispidulin is a neuroprotective agent with clinical potential against IR-induced neurological injury.