title: N-Butylphthalide (NBP) ameliorated cerebral ischemia reperfusion-induced brain injury via HGF-regulated TLR4/NF-κB signaling pathway.
abstract: N-Butylphthalide (NBP) has been known to have potential neuroprotective effects in Alzheimer's disease and stroke animal models. Hepatocyte-growth factor (HGF), with strong angiogenic properties, exerted protective role in brain injury. The present study was aimed to investigate the possible anti-inflammatory effects of NBP on the brain injury of rats with cerebral ischemia reperfusion (IR) and astrocytes activation induced by lipopolysaccharide (LPS) treatment. Our results showed that cerebral IR induced brain damage with down-regulation of HGF and astrocytes activation. NBP treatment significantly increased HGF expression and activated cMet/PI3K/AKT signaling pathway, stimulating mTOR activity and suppressing apoptosis in brain tissues. Also NBP inhibited pro-inflammatory cytokines expression, including IL-6, IL-1β, and TNFα, via TLR4/NF-κB suppression. Anti-HGF treatment enhanced TLR4 expression while HGF could suppress TLR4 activation and its down-streaming signals, attenuating inflammation finally. Notably, NBP up-regulated HGF and down-regulated TLR4 expression significantly in the astrocytes combined with the treatment of TLR4 inhibitor than the cells only treated with TLR4 inhibitor, suggesting that NBP could further suppress TLR4 activation, suggesting that NBP might impede TLR4 through up-regulating HGF expression. These results suggested that NBP treatment significantly ameliorated cerebral IR-induced brain injury by inhibiting TLR4/NF-κB-associated inflammation regulated by HGF.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan Province, 450052 PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan Province, 450052 PR China.
authors.forename: Zhen-Fang
authors.initials: ZF
authors.lastname: Guo
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan Province, 450052 PR China. Electronic address: xuyuming450052@163.com.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Xu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan Province, 450052 PR China.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Li
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan Province, 450052 PR China.
authors.forename: Jing-Gui
authors.initials: JG
authors.lastname: Song
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001572:Benzofurans; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D017228:Hepatocyte Growth Factor; C027125:3-n-butylphthalide
keywords: Brain injury; HGF; Inflammation; N-Butylphthalide (NBP); TLR4/NF-κB