MCC950, the selective inhibitor of nucleotide oligomerization domain-like receptor protein-3 inflammasome, protects mice against traumatic brain injury

Saifudeen Ismael, Sanaz Nasoohi, Tauheed Ishrat

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1294-1303
Number of pages10
JournalJournal of Neurotrauma
Volume35
Issue number11
DOIs
StatePublished - Jun 1 2018

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Inflammasomes
Nucleotides
Proteins
Caspase 1
Traumatic Brain Injury
Poly(ADP-ribose) Polymerases
NF-kappa B
Brain Edema
Inbred C57BL Mouse
Immunoblotting
Caspase 3
Young Adult
Therapeutics
NLR Proteins
Apoptosis

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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MCC950, the selective inhibitor of nucleotide oligomerization domain-like receptor protein-3 inflammasome, protects mice against traumatic brain injury. / Ismael, Saifudeen; Nasoohi, Sanaz; Ishrat, Tauheed.

In: Journal of Neurotrauma, Vol. 35, No. 11, 01.06.2018, p. 1294-1303.

Research output: Contribution to journalArticle

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