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

被引：77

作者：

Suzuki, Yukiya ^{[1
]}

Hattori, Kozo ^{[2
]}

Hamanaka, Junya ^{[1
]}

Murase, Tetsuji ^{[2
]}

Egashira, Yusuke ^{[1
,3
]}

Mishiro, Keisuke ^{[1
]}

Ishiguro, Mitsunori ^{[1
,3
]}

Tsuruma, Kazuhiro ^{[1
]}

Hirose, Yoshinobu ^{[4
]}

Tanaka, Hiroyuki ^{[5
]}

Yoshimura, Shinichi ^{[3
]}

Shimazawa, Masamitsu ^{[1
]}

Inagaki, Naoki ^{[5
]}

Nagasawa, Hideko ^{[2
]}

Iwama, Toru ^{[3
]}

Hara, Hideaki ^{[1
]}

机构：

[1] Gifu Pharmaceut Univ, Dept Biofunct Evaluat, Gifu 5011196, Japan

[2] Gifu Pharmaceut Univ, Dept Organ & Med Chem, Gifu 5011196, Japan

[3] Gifu Univ, Grad Sch Med, Dept Neurosurg, Gifu 5011194, Japan

[4] Gifu Univ Hosp, Dept Pathol, Gifu 5011194, Japan

[5] Gifu Pharmaceut Univ, Dept Bioact Mol, Gifu 5011196, Japan

来源：

SCIENTIFIC REPORTS | 2012年 / 2卷

基金：

日本学术振兴会;

关键词：

TOLL-LIKE RECEPTOR-4; CEREBRAL-ISCHEMIA; ISCHEMIA/REPERFUSION INJURY; TRANSDUCTION INHIBITOR; REPERFUSION INJURY; CUTTING EDGE; CELL-DEATH; TLR4; ACTIVATION; MICE;

D O I：

10.1038/srep00896

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 mu g) 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.

引用

页数：9

共 41 条

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