Inflammasomes have been identified as intracellular multiprotein complexes that tightly regulate the innate immune response and the production of pro-inflammatory cytokines such as IL-1β and IL-18. The inflammasomes share a similar structure and are typically formed by a cytosolic pattern-recognition receptor, an adaptor protein, and an effector component (caspase-1). Among the known inflammasomes, the NLRP3 inflammasome is the most extensively studied and widely implicated regulator of caspase-1 activation, the maturation and production of IL-1β and IL-18. Notably, numerous recent studies have indicated a critical role for NLRP3 inflammasome and IL-1β in the pathogenesis of many disorders such as AMI, TBI, and AD, among others. However specific NLRP3 inflammasome inhibitors are lacking.<br/>Recently we have designed a specific NLRP3 inflammasome inhibitor template based on the structure of glyburide. Biological characterization demonstrated that this small molecule NLRP3 inflammasome inhibitor inhibits the production of IL-1beta, the activation of caspase-1. These effects are specifically through the inhibition of the NLRP3 inflammasome. Furthermore, we demonstarted in a mouse AMI model that treatment with this NLRP3 inflammasome inhibitor reduced the infarct size and cardiac injuries as well as limited the left ventricular dysfunction following ischemic and non-ischemic injuries. We also demonstrated that this small molecule NLRP3 inflammasome inhibitor can penetrate the BBB and protect neurons from TBI. Most importantly treatment with this inhibitor can improve motor and cognitive functions following TBI in rats. Collectively these findings strongly suggest that inhibition of the NLRP3 inflammasome with small molecule inhibitors is a promisng new strategy for pathological disordes that involve the innate immune and NLRP3 inflammasome systems. Detailed in vitro and in vivo studies and SAR studies will be presented.

Development of novel NLRP3 inflammasome inhibitors and their potential application

249th National Meeting (2015)

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