Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.
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ABSTRACT: Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60?min tMCAO followed by intraperitoneal administration of MCC950 (50?mg/kg) or saline at 1?h and 3?h post-occlusion. After 24?h of I/R, mice were tested for neurological outcome and were sacrificed for the analysis of infarct size and estimating NLRP3-inflammasome and apoptotic markers as well. Spectrophotometric method was used to determine hemoglobin (Hb) content as a marker of intracerebral hemorrhage. MCC950-treated mice showed a substantial reduction in infarction, edema and Hb content compared to saline controls in parallel with improved neurological deficits. MCC950 reduced expression of NLRP3-inflammasome cleavage products Caspase-1 and interlukin-1? (IL-1?) in penumbral region. These protective effects of MCC950 were associated with decreased TNF-? levels as well as poly (ADP-ribose) polymerase (PARP) and Caspase-3 cleavage and paralleled less phosphrylated NF?Bp65 and I?B? levels. Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 has therapeutic potential in ischemic stroke models. Further investigations into the therapeutic efficacy and protocols are needed to confirm whether MCC950 treatment could be a promising candidate for clinical trials.
SUBMITTER: Ismael S
PROVIDER: S-EPMC5899150 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
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