NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development

Int J Mol Sci. 2024 May 31;25(11):6078. doi: 10.3390/ijms25116078.

Abstract

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.

Keywords: ASC; NLRP3 inflammasome; antiseizure medication; caspase-1; epilepsy; epileptogenesis; interleukin-1β; neuroinflammation.

Publication types

  • Review

MeSH terms

  • Animals
  • Anticonvulsants* / pharmacology
  • Anticonvulsants* / therapeutic use
  • Drug Development
  • Drug Discovery* / methods
  • Epilepsy* / drug therapy
  • Humans
  • Inflammasomes* / antagonists & inhibitors
  • Inflammasomes* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Anticonvulsants
  • Inflammasomes
  • NLRP3 protein, human

Grants and funding

This work was supported by the Research Department of the Kansas City VA Medical Center (KCVAMC) and Midwest Veterans Biomedical Research Foundation (MVBRF) at KCVAMC, Kansas City, MO, 64128.