Effects of NLRP3 inflammasome blockade on postresuscitation cerebral function in a rat model of cardiopulmonary resuscitation

• Main Authors: Guanghui Zheng, Jing Xu, Fenglian He, Juntao Hu, Weiwei Ge, Xianfei Ji, Changsheng Wang, Jennifer L. Bradley, Mary Ann Peberdy, Joseph P. Ornato, Stefano Toldo, Tong Wang, Wanchun Tang
• Format: Article
• Language: English
• Published: Elsevier 2021-11-01
• Series: Biomedicine & Pharmacotherapy
• Subjects: Cardiac arrest; Cerebral function; Microcirculation; NLRP3 inflammasome; MCC950; Postresuscitation
• Online Access: http://www.sciencedirect.com/science/article/pii/S0753332221008763

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.