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

• Published in: Scientific reports Vol. 2; no. 1; p. 896
• Main Authors: Suzuki, Yukiya, Hattori, Kozo, Hamanaka, Junya, Murase, Tetsuji, Egashira, Yusuke, Mishiro, Keisuke, Ishiguro, Mitsunori, Tsuruma, Kazuhiro, Hirose, Yoshinobu, Tanaka, Hiroyuki, Yoshimura, Shinichi, Shimazawa, Masamitsu, Inagaki, Naoki, Nagasawa, Hideko, Iwama, Toru, Hara, Hideaki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.11.2012; Nature Publishing Group
• Subjects: 631/154; 631/378/340; 631/378/87; 692/700/139/422; Animals; Apoptosis; Apoptosis - drug effects; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Case-Control Studies; Cell Death - drug effects; Cerebral blood flow; Disease Models, Animal; Female; Humanities and Social Sciences; Humans; Infarction, Middle Cerebral Artery - drug therapy; Inflammation; Ischemia; Male; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Metalloproteinase; Mice; Mice, Inbred Strains; Middle Aged; multidisciplinary; NADPH Oxidase 4; NADPH Oxidases - metabolism; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; NF-kappa B - metabolism; NF-κB protein; NOX4 protein; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism; Reperfusion; Reperfusion Injury - prevention & control; Rodents; Science; Signal Transduction - drug effects; Stroke; Sulfonamides - pharmacology; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Young Adult
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep00896

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.