A novel small molecular NLRP3 inflammasome inhibitor alleviates neuroinflammatory response following traumatic brain injury

J Neuroinflammation. 2019 Apr 11;16(1):81. doi: 10.1186/s12974-019-1471-y.

Abstract

Background: Neuroinflammation is an essential player in many neurological diseases including traumatic brain injury (TBI). Recent studies have identified that inflammasome complexes are responsible for inflammatory responses in many pathological conditions. Inflammasomes are intracellular multiprotein complexes which regulate the innate immune response, activation of caspase-1, production of pro-inflammatory cytokines IL-1β and IL-18, and induction of cell death (pyroptosis). Among inflammasome family members, the nucleotide-binding domain leucine-rich repeats family protein 3 (NLRP3) is the most extensively studied and its activation is induced following TBI. As a novel target, drug development targeting the formation and activation of NLRP3 inflammasome is a prospective therapy for TBI. We have recently developed a small molecule JC124 with specificity on NLRP3 inflammasome. In this study, we explored the therapeutic value of JC124 for TBI treatment.

Methods: Adult male Sprague-Dawley rats were subjected to a moderate cortical impact injury. Following TBI, animals received 4 doses of JC124 treatment with the first dose starting at 30 min, the second dose at 6 h after TBI, the third and fourth doses at 24 or 30 h following TBI, respectively. Animals were sacrificed at 2 days post-injury. Brain tissues were processed either for ELISA and western blotting analysis for inflammatory response, or for histological examination to assess degenerative neurons, acute inflammatory cell response and lesion volume.

Results: We found that post-injury treatment with JC124 significantly decreased the number of injury-induced degenerating neurons, inflammatory cell response in the injured brain, and cortical lesion volume. Injured animals treated with JC124 also had significantly reduced protein expression levels of NLRP3, ASC, IL-1 beta, TNFα, iNOS, and caspase-1.

Conclusion: Our data suggest that our novel NLRP3 inhibitor has a specific anti-inflammatory effect to protect the injured brain following TBI.

Keywords: Cytokines; Inflammasome; NLRP3; Neuroinflammation; Traumatic brain injury.

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain Injuries, Traumatic / complications*
  • CD11b Antigen / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Encephalitis / drug therapy*
  • Encephalitis / etiology*
  • Fluoresceins / metabolism
  • Glyburide / therapeutic use*
  • HLA-DR alpha-Chains / metabolism
  • Inflammasomes / chemistry
  • Inflammasomes / therapeutic use*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / blood
  • Male
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • CD11b Antigen
  • Fluoresceins
  • HLA-DR alpha-Chains
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • fluoro jade
  • Glyburide