Biological and therapeutic significance of targeting NLRP3 inflammasome in the brain and the current efforts to develop brain-penetrant inhibitors

Abstract

NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a pivotal regulator of the innate immune system, orchestrates inflammatory responses implicated in neurodegenerative and inflammatory diseases. Over the past 20 years, the exploration of NLRP3 activation pathways has advanced significantly. Upon NLRP3 activation, it initiates the formation of a cytosolic multiprotein complex known as the inflammasome. This complex activates caspase-1, which then processes proinflammatory cytokines IL-1β and IL-18 and leads to gasdermin-mediated cell death, pyroptosis. Structural insights into NLRP3 inflammasome assembly and caspase-1 activation have spurred development of novel small molecule inhibitors targeting this pathway, aiming to mitigate excessive inflammation without compromising immune surveillance. The initial NLRP3 inhibitor reported was glyburide, an FDA-approved antidiabetic drug of the sulfonylurea class, which was found to inhibit the release of IL-1β induced by stimuli in human monocytes and murine macrophages. Subsequently, MCC950 (also known as CRID3), a direct NLRP3 inhibitor, was discovered. While showing promising results in preclinical and clinical trials for treating diseases, higher doses of MCC950 led to elevated transaminase levels and hepatotoxicity concerns. Recent studies using MCC950 as a research tool have prompted the development of safer and more effective NLRP3 inhibitors, including a series of compounds currently undergoing clinical trials, highlighting the potential of NLRP3 inhibitors in attenuating disease progression and improving therapeutic outcomes. In this chapter, we delve into the latest progress in understanding the mechanism of NLRP3 inflammasome activation and its roles in the pathophysiology of neurological diseases. We also summarize recent development of small molecule NLRP3 inhibitors along with the associated obstacles and concerns.