Protective Effects of Remimazolam on Cerebral Ischemia/Reperfusion Injury in Rats by Inhibiting of NLRP3 Inflammasome-Dependent Pyroptosis

Abstract

Min Shi,* Jing Chen,* Tianxiao Liu,* Weixin Dai, Zhan Zhou, Lifei Chen, Yubo Xie Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yubo Xie, Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuang-yong Road, Nanning, 530021, People’s Republic of China, Tel +86 186 7795 8208, Email xybdoctor@163.comIntroduction: Remimazolam is a novel benzodiazepine γ-aminobutyric acid A (GABAa) receptor agonist used for sedation and the induction as well as maintenance of general anesthesia. Previous research proved that anesthetic agents acting on GABAa receptor, such as thiopentone, propofol and midazolam, have protective actions for cerebral ischemia/reperfusion (I/R) injury. We here probed into remimazolam for its protective effect and potential mechanism of action against cerebral I/R injury.Material and Methods: A rat model of middle cerebral artery occlusion (MCAO) with focal transient cerebral I/R injury was established and was given tail vein injection of gradient remimazolam (5, 10, 20 mg/kg) after 2 h of ischemia. Following 24 h of reperfusion, neurological function, brain infarct volume, morphology of cerebral cortical neurons, and expressions of corticocerebral NLRP3, ASC, caspase-1, GSDMD, IL-1β and IL-18 were evaluated.Results: The results showed that remimazolam could effectively improve the neurological dysfunction, reduce the infarct volume and alleviate the damage of cortical neurons after I/R injury. Notably, the expression of NLRP3 inflammasome pathway was down-regulated, suggesting that remimazolam exerted protective actions on I/R injury by suppressing pyroptosis with decreased expression and release of inflammatory factors, and the involvement of the NLRP3 inflammasome pathway might be the core during that process. Overall, our results indicate that NLRP3 inflammation is a promising target.Conclusion: Based on this mechanism, remimazolam may be one of the ideal anesthetic drugs for patients with ischemic stroke.Keywords: remimazolam, NLRP3 inflammasome, ischemia/reperfusion injury, I/R, pyroptosis, inflammation