Inhibition of NLRP3 Inflammasome: A Prospective Target for the Treatment of Ischemic Stroke.

Ya-Shuo Feng,Feng Zhang,Ying Xing,Man-Man Wang,Zi-Xuan Tan,Fang Dong

doi:10.3389/fncel.2020.00155

Abstract

Stroke is one of the major devastating diseases with no effective medical therapeutics. Because of the high rate of disability and mortality among stroke patients, new treatments are urgently required to decrease brain damage following a stroke. In recent years, the inflammasome is a novel breakthrough point that plays an important role in the stroke, and the inhibition of inflammasome may be an effective method for stroke treatment. Briefly, inflammasome is a multi-protein complex that causes activation of caspase-1 and subsequent production of pro-inflammatory factors including interleukin (IL)-18 and IL-1β. Among them, the NLRP3 inflammasome is the most typical inflammasome, which can detect cell damage and mediate inflammatory response to tissue damage in ischemic stroke. The NLRP3 inflammasome has become a key mediator of post-ischemic inflammation, leading to a cascade of inflammatory reactions and cell death eventually. Thus, NLRP3 inflammasome is an ideal therapeutic target due to its important role in the inflammatory response after ischemic stroke. In this mini review article, we will summarize the structure, assembly, and regulation of NLRP3 inflammasome, the role of NLRP3 inflammasome in ischemic stroke, and several treatments targeting NLRP3 inflammasome in ischemic stroke. The further understanding of the mechanism of NLRP3 inflammasome in patients with ischemic stroke will provide novel targets for the treatment of cerebral ischemic stroke patients.

Highlights

Nowadays, stroke is a major reason for long-term disability and death worldwide, which can lead to a heavy burden on patients and the whole society, especially in low- and middle-income countries (Feigin et al, 2017; Lapchak and Zhang, 2017)
Increasing evidence has shown that inhibition of NOD-like receptor pyrin domain containing 3 (NLRP3) may significantly reduce the infarct volume and improve neurological function in cerebral ischemic animal models
The discovery of NLRP3 inflammasome provides a new way to study the molecular mechanism of ischemic stroke

Summary

INTRODUCTION

Stroke is a major reason for long-term disability and death worldwide, which can lead to a heavy burden on patients and the whole society, especially in low- and middle-income countries (Feigin et al, 2017; Lapchak and Zhang, 2017). The generation of ROS can activate both cerebral inflammatory reactions and NLRP3 inflammasome, triggering neuronal cell injury, brain edema, and neural dysfunction (Wang et al, 2007; Minutoli et al, 2016). Mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways played an important role in regulating the expression and activation of NLRP3 inflammasomes in brain tissue and primary cortical neurons during ischemia (Fann et al, 2018). IMM-H004, a novel coumarin derivative, could decrease the expression level of chemokine-like factor 1 (CKLF1) combining with C-C chemokine receptor 4, further inhibiting the NLRP3 inflammasome activation and inflammation, thereby exerting therapeutic effects on rats following ischemic stroke (Ai et al, 2019). Many medicants have positive effects on improving neurological dysfunction, infarct volume, and cerebral edema in ischemic stroke model via suppressing NLRP3 pathways

Molecular Inhibitors

Intravenous Immunoglobulin

Other Therapeutic Methods

Transient MCAO mice model

Findings

CONCLUSION