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

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

Biomedicine & Pharmacotherapy (Nov 2021)

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

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

Affiliations

Guanghui Zheng: 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
Jing Xu: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA
Fenglian He: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA
Juntao Hu: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA
Weiwei Ge: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA
Xianfei Ji: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA
Changsheng Wang: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA
Jennifer L. Bradley: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA
Mary Ann Peberdy: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA; Departments of Internal Medicine and Emergency Medicine, Virginia Commonwealth University Health System, Richmond,VA, USA
Joseph P. Ornato: Weil Institute of Emergency and Critical Care Research, Virginia Commonwealth University, Richmond, VA, USA; Department of Emergency Medicine, Virginia Commonwealth University Health System, Richmond,VA, USA
Stefano Toldo: Department of Internal Medicine, Virginia Commonwealth University Health System, Richmond,VA, USA
Tong Wang: Department of Emergency, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Corresponding author.
Wanchun Tang: 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; Department of Emergency Medicine, Virginia Commonwealth University Health System, Richmond,VA, USA; Correspondence to: Weil Institute of Emergency and Critical Care Research at VCU, Box 980266, Sanger Hall, 1101 E Marshall St, Richmond, VA 23298-0279, USA.

Journal volume & issue: Vol. 143
p. 112093

Abstract

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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.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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