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Sci Rep. 2012;2:896. doi: 10.1038/srep00896. Epub 2012 Nov 28.

Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia.

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  • 1Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University , Gifu 501-1196, Japan.

Abstract

Recent data have shown that TLR4 performs a key role in cerebral ischemia-reperfusion injury which serves as the origin of the immunological inflammatory reactions. However, the therapeutic effects of pharmacological inhibitions of TLR4 and its immediate down-stream pathway remain to be uncovered. In the present study, on mice, intracerebroventricular injection of resatorvid (TLR4 signal inhibitor; 0.01 μg) significantly reduced infarct volume and improved neurological score after middle cerebral artery occlusion and reperfusion. The levels of phospho-p38, nuclear factor-kappa B, and matrix metalloproteinase 9 expressions were significantly suppressed in the resatorvid-treated group. In addition, NOX4 associates with TLR4 after cerebral ischemia-reperfusion seen in mice and human. Genetic and pharmacological inhibitions of TLR4 each reduced NOX4 expression, leading to suppression of oxidative/nitrative stress and of neuronal apoptosis. These data suggest that resatorvid has potential as a therapeutic agent for stroke since it inhibits TLR4-NOX4 signaling which may be the predominant causal pathway.

PMID:
23193438
[PubMed - indexed for MEDLINE]
PMCID:
PMC3508453
Free PMC Article

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