Zheng Guanghui, Xu Jing, He Fenglian, Hu Juntao, Ge Weiwei, Ji Xianfei, Wang Changsheng, Bradley Jennifer L, Peberdy Mary Ann, Ornato Joseph P, Toldo Stefano, Wang Tong, Tang Wanchun
Department of Emergency, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA; Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-Sen University, Guangzhou, China.
Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA.
Biomed Pharmacother. 2021 Nov;143:112093. doi: 10.1016/j.biopha.2021.112093. Epub 2021 Aug 30.
Cardiac arrest (CA) remains a major public health issue. Inflammatory responses with overproduction of interleukin-1β regulated by NLRP3 inflammasome activation play a crucial role in cerebral ischemia/reperfusion injury. We investigated the effects of the selective NLRP3-inflammasome inhibitor MCC950 on post-resuscitation cerebral function and neurologic outcome in a rat model of cardiac arrest. Thirty-six male rats were randomized into the MCC950 group, the control group, or the sham group (N = 12 of each group). Each group was divided into a 6 h non-survival subgroup (N = 6) and a 24 h survival subgroup (N = 6). Ventricular fibrillation (VF) was electrically induced and untreated for 6 min, followed by 8 min of precordial compressions and mechanical ventilation. Resuscitation was attempted with a 4J defibrillation. Either MCC950 (10 mg/kg) or vehicle was injected intraperitoneally immediately after the return of spontaneous circulation (ROSC). Rats in the sham group underwent the same surgical procedures without VF and CPR. Brain edema, cerebral microcirculation, plasma interleukin Iβ (IL-1β), and neuron-specific enolase (NSE) concentration were measured at 6 h post-ROSC of non-survival subgroups, while 24 h survival rate, neurological deficits were measured at 24 h post-ROSC of survival subgroups. Post-resuscitation brain edema was significantly reduced in animals treated with MCC950 (p < 0.05). Cerebral perfused vessel density (PVD) and microcirculatory flow index (MFI) values were significantly higher in the MCC950 group compared with the control group (p < 0.05). The plasma concentrations of IL-1β and NSE were significantly decreased in animals treated with MCC950 compared with the control group (p < 0.05). 24 h-survival rate and neurological deficits score (NDS) was also significantly improved in the MCC950 group compared with the control group (p < 0.05). NLRP3 inflammasome blockade with MCC950 at ROSC reduces the circulatory level of IL-1β, preserves cerebral microcirculation, mitigates cerebral edema, improves the 24 h-survival rate, and neurological deficits.
心脏骤停（CA）仍然是一个重大的公共卫生问题。由NLRP3炎性小体激活调节的白细胞介素-1β过度产生所引发的炎症反应在脑缺血/再灌注损伤中起关键作用。我们研究了选择性NLRP3炎性小体抑制剂MCC950对心脏骤停大鼠模型复苏后脑功能和神经学结局的影响。36只雄性大鼠被随机分为MCC950组、对照组或假手术组（每组n = 12）。每组又分为6小时非存活亚组（n = 6）和24小时存活亚组（n = 6）。通过电诱导室颤（VF）并持续6分钟不进行处理，随后进行8分钟的心前区按压和机械通气。尝试用4J除颤进行复苏。在自主循环恢复（ROSC）后立即腹腔注射MCC950（10mg/kg）或赋形剂。假手术组大鼠接受相同的手术操作，但不诱发VF和进行心肺复苏。在非存活亚组ROSC后6小时测量脑水肿、脑微循环、血浆白细胞介素Iβ（IL-1β）和神经元特异性烯醇化酶（NSE）浓度，而在存活亚组ROSC后24小时测量24小时存活率和神经功能缺损。用MCC950处理的动物复苏后脑水肿明显减轻（p < 0.05）。与对照组相比，MCC950组的脑灌注血管密度（PVD）和微循环血流指数（MFI）值明显更高（p < 0.05）。与对照组相比，用MCC950处理的动物血浆中IL-1β和NSE的浓度明显降低（p < 0.05）。与对照组相比，MCC950组的24小时存活率和神经功能缺损评分（NDS）也明显改善（p < 0.05）。在ROSC时用MCC950阻断NLRP3炎性小体可降低IL-1β的循环水平，保护脑微循环，减轻脑水肿，提高24小时存活率，并改善神经功能缺损。
