Small molecule inhibitors of NLRP3 inflammasome and GSK-3β in the management of traumatic brain injury: A review

Abstract

Traumatic brain injury (TBI) is a debilitating mental condition which causes physical disability and morbidity worldwide. TBI may damage the brain by direct injury that subsequently triggers a series of neuroinflammatory events. The activation of NLRP3 inflammasome and dysregulated host immune system has been documented in various neurological disorders such as TBI, ischemic stroke and multiple sclerosis. The activation of NLRP3 post-TBI increases the production of pro-inflammatory cytokines and caspase-1, which are major drivers of neuroinflammation and apoptosis. Similarly, GSK-3β regulates apoptosis through tyrosine kinase and canonical Wnt signalling pathways. Thus, therapeutic targeting of NLRP3 inflammasome and GSK-3β has emerged as promising strategies for regulating the post-TBI neuroinflammation and neurobehavioral disturbances. In this review, we discuss the identification & development of several structurally diverse and pharmacologically interesting small molecule inhibitors for targeting the NLRP3 inflammasome and GSK-3β in the management of TBI.