Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan Province, China; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha 410008, Hunan Province, China.
Department of Anesthesiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 Xinjiang, Uygur Autonomous Region, China.
Exp Neurol. 2022 Nov;357:114197. doi: 10.1016/j.expneurol.2022.114197. Epub 2022 Aug 4.
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 postconditioning in OGD/R. Additionally, the neuroprotection of Chrysophanol postconditioning was also abolished by gain-of-function analyses of TRAF6. Finally, the results demonstrated that Chrysophanol postconditioning suppressed the interaction between TRAF6 and NLRP3. Taken together, our findings revealed that Chrysophanol postconditioning was protective against CIRI by inhibiting NLRP3-related pyroptosis in a TRAF6-dependent manner.
经历心脏骤停（CA）后脑损伤的个体经历更高的死亡率和更严重的功能障碍。神经炎症已被确定为 CA 后脑缺血再灌注损伤（CIRI）的一个重要因素。细胞焦亡通过引发过度炎症损伤诱导神经元死亡。大黄素具有强大的抗炎作用，可预防 CIRI。本研究旨在评估大黄素后处理对 CIRI 诱导的细胞焦亡性细胞死亡的影响，并探讨其潜在机制。通过 CA 和随后的心肺复苏在大鼠中诱导 CIRI，并将 PC12 细胞暴露于氧葡萄糖剥夺/再氧合（OGD/R）以模拟体外 CIRI。结果发现，CA 后脑损伤导致组织病理学变化和神经功能结果显示出明显的脑损伤。在体内和体外 CIRI 模型中也证实了细胞焦亡的存在。此外，我们进一步证实，大黄素，大黄的主要生物活性成分，显著抑制了细胞焦亡相关蛋白的表达，例如 NLRP3、ASC、裂解的胱天蛋白酶-1 和 N 端 GSDMD，并抑制了肿瘤坏死因子受体相关因子 6（TRAF6）的表达。此外，NLRP3 过表达使大黄素后处理的神经保护作用失效，表明细胞焦亡是 OGD/R 中大黄素后处理调节的主要神经元死亡途径。此外，TRAF6 的功能获得分析也消除了大黄素后处理的神经保护作用。最后，结果表明大黄素后处理抑制了 TRAF6 和 NLRP3 之间的相互作用。总之，我们的研究结果表明，大黄素后处理通过依赖于 TRAF6 的方式抑制 NLRP3 相关的细胞焦亡来保护 CIRI。
