Chrysophanol postconditioning attenuated cerebral ischemia-reperfusion injury induced NLRP3-related pyroptosis in a TRAF6-dependent manner

作者：Pingping Xia, Murat Marjan, Zhuoyi Liu, Wanqing Zhou, Qian Zhang, Cheng Chen, Minxi Zhao, Yuanyuan Tao, Zhihua Wang, Zhi Ye · 发表于：Experimental Neurology · 年份：2022 · DOI：10.1016/j.expneurol.2022.114197 · 被引用次数：28 · 研究领域：Inflammasome and immune disorders、Cardiac Arrest and Resuscitation、Mitochondrial Function and Pathology

Individuals who suffer from post-CA (cardiac arrest) brain injury experience higher mortality and more severe functional disability. Neuroinflammation has been identified as a vital factor in cerebral ischemia-reperfusion injury (CIRI) following CA. Pyroptosis induces neuronal death by triggering an excessive inflammatory injury. Chrysophanol possesses robust anti-inflammatory features, and it is protective against CIRI. The purpose of this research was to assess the effect of Chrysophanol postconditioning on CIRI-induced pyroptotic cell death, and to explore its underlying mechanisms. CIRI was induced in rats by CA and subsequent cardiopulmonary resuscitation, and PC12 cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to imitate CIRI in vitro. It was found that post-CA brain injury led to a notable cerebral damage revealed by histopathological changes and neurological outcomes. The existence of pyroptosis was also confirmed in in vivo and in vitro CIRI models. Moreover, we further confirmed that Chrysophanol, the main bioactive ingredient of Rhubarb, significantly suppressed expressions of pyroptosis-associated proteins, e.g., NLRP3, ASC, cleaved-caspase-1 and N-terminal GSDMD, and inhibited the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6). Furthermore, NLRP3 overexpression neutralized the neuroprotection of Chrysophanol postconditioning, suggesting that pyroptosis was the major neuronal death pathway modulated by Chrysophanol...