title: TLR4 inhibitor resatorvid provides neuroprotection in experimental traumatic brain injury: implication in the treatment of human brain injury.
abstract: Toll-like receptor 4 (TLR4) is considered to play an important role in neuronal death in animal models and could be an important therapeutic target following traumatic brain injury (TBI). Resatorvid is a small molecule, commonly accepted to inhibit TLR4-mediated pathway. The purpose of this study was to investigate the neuroprotective effect of resatorvid after TBI. Our data revealed that inhibition of TLR4 by resatorvid attenuated the development of TBI in mouse model. And we found that resatorvid administration dramatically reduced neuronal apoptosis. To investigate the cellular mechanism, we evaluated the expression of transforming growth factor-β-activated kinase 1 (TAK1), which plays a crucial role in TLR4 signal transduction pathway and is activated by phosphorylation in response to TBI. In addition, enzyme-linked immunosorbent assay was used to determine the expression of tumor necrosis factor-α (TNF-α) and interlukin-1β (IL-1β) at 24h after injury. Our results showed that resatorvid treatment significantly reduced the protein levels of TAK1, p-TAK1, TNF-α, and IL-1β compared with vehicle treatment. Importantly, the delayed therapy (4h post injury) once daily consecutively for 5days ameliorated brain damage and improved neurological recovery, suggesting that this drug has a wide therapeutic time window. Clinically, we observed that TLR4 and TAK1 expression was significantly increased in human contusion specimens after TBI. These data provide an experimental rationale for the evaluation of TLR4 as a clinical target and therapeutic implication of resatorvid in human traumatic brain injury.
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Dingding
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Mengliang
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu Province, PR China.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu Province, PR China. Electronic address: likuanyu@nju.edu.cn.
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China. Electronic address: hang_neurosurgery@163.com.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Hang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001930:Brain Injuries / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: D018696:Neuroprotective Agents; D013449:Sulfonamides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
keywords: Apoptosis; Resatorvid; Toll-like receptor 4; Traumatic brain injury