MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury

J Neurotrauma. 2018 Jun 1;35(11):1294-1303. doi: 10.1089/neu.2017.5344. Epub 2018 Apr 2.

Abstract

Nucleotide oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome may intimately contribute to sustaining damage after traumatic brain injury (TBI). This study aims to examine whether specific modulation of NLPR3 inflammasome by MCC950, a novel selective NLRP3 inhibitor, confers protection after experimental TBI. Unilateral cortical impact injury was induced in young adult C57BL/6 mice. MCC950 (50 mg/kg, intraperitoneally) or saline was administration at 1 and 3 h post-TBI. Animals were tested for neurological function and then sacrificed at 24 or 72 h post-TBI. Immunoblotting and histological analysis were performed to identify markers of NLRP3 inflammasome and proapoptotic activity in pericontusional areas of the brains at 24 or 72 h post-TBI. MCC950 treatment provided a significant improvement in neurological function and reduced cerebral edema in TBI animals. TBI upregulated NLRP3, apoptosis-associated speck-like adapter protein (ASC), cleaved caspase-1, and interlukein-1β (IL-1β) in the perilesional area. MCC950 efficiently repressed caspase-1 and IL-1β with a transient effect on ASC and NLRP3 post-TBI. MCC950 treatment also provided protection against proapoptotic activation of poly (ADP-ribose) polymerase and caspase-3 associated with TBI. A concurrent inhibition of inflammasome priming was also detectable at the nuclear factor kappa B/p65 and caspase-1 level. Our findings support the implication of NLRP3 inflammasome in the pathogenesis of TBI and further suggests the therapeutic potential of MCC950.

Keywords: MCC950; NLRP3-inflammasome inhibitor; edema; inflammation; neurological deficits; traumatic brain injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Injuries, Traumatic / pathology*
  • Furans / pharmacology*
  • Heterocyclic Compounds, 4 or More Rings
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology*
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Sulfonamides / pharmacology*
  • Sulfones

Substances

  • Furans
  • Heterocyclic Compounds, 4 or More Rings
  • MCC-950
  • Neuroprotective Agents
  • Nod-like receptor protein 3 inflammasome, mouse
  • Receptors, Cell Surface
  • Sulfonamides
  • Sulfones