title: Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia.
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.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University , Gifu 501-1196, Japan.
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kozo
authors.initials: K
authors.lastname: Hattori
authors.forename: Junya
authors.initials: J
authors.lastname: Hamanaka
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Murase
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Egashira
authors.forename: Keisuke
authors.initials: K
authors.lastname: Mishiro
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hirose
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Inagaki
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Toru
authors.initials: T
authors.lastname: Iwama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse; D020780:Matrix Metalloproteinase 9