title: Neuroprotective Effects of Resatorvid Against Traumatic Brain Injury in Rat: Involvement of Neuronal Autophagy and TLR4 Signaling Pathway.
abstract: Accumulating evidence indicates that autophagy and inflammatory responses contributes to secondary brain injury after traumatic brain injury (TBI), and toll-like receptor 4 (TLR4) is considered to involvement of this cascade and plays an important role. The present study was designed to determine the hypothesis that administration of resatorvid (TAK-242), a TLR4 antagonist, might provide a neuroprotective effect by inhibit TLR4-mediated pathway in a TBI rat model. Rat subjected to controlled cortical impact injury were injected with TAK-242 (0.5 mg/kg, i.v. injected) 10 min prior to injury. The results demonstrated that TAK-242 treatment significantly attenuated TBI-induced neurons loss, brain edema, and neurobehavioral impairment in rats. Immunoblotting analysis showed that TAK-242 treatment reduced TBI-induced TLR4, Beclin 1, and LC3-II levels, and maintained p62 levels at 24 h. Double immunolabeling demonstrated that LC3 dots co-localized with the hippocampus pyramidal neurons, and TLR4 was localized with the hippocampus neurons and astrocytes. In addition, the expression of TLR4 downstream signaling molecules, including MyD88, TRIF, NF-κB, TNF-α, and IL-1β, was significantly downregulated in hippocampus tissue by Western blot analysis. In conclusion, our findings indicate that pre-injury treatment with TAK-242 could inhibit neuronal autophagy and neuroinflammation responses in the hippocampus in a rat model of TBI. The neuroprotective effects of TAK-242 may be related to modulation of the TLR4-MyD88/TRIF-NF-κB signaling pathway. Furthermore, the study also suggests that TAK-242, an attractive potential drug, may be a promising drug candidate for TBI.
authors.affiliation: Department of Surgery, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, People's Republic of China.|Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: School of Basic Medical Science, North China University of Science and Technology, Tangshan, People's Republic of China.
authors.forename: Junling
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, Tangshan Workers' Hospital, Tangshan, 063000, Hebei, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cui
authors.affiliation: School of Basic Medical Science, North China University of Science and Technology, Tangshan, People's Republic of China.
authors.forename: Minghang
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Basic Medical Science, North China University of Science and Technology, Tangshan, People's Republic of China.
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Surgery, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, People's Republic of China.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cui
authors.affiliation: Department of Surgery, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, People's Republic of China. jzhcuidr2001@163.com.|Department of Neurosurgery, Tangshan Workers' Hospital, Tangshan, 063000, Hebei, People's Republic of China. jzhcuidr2001@163.com.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Cui
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D013449:Sulfonamides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
keywords: Autophagy; Neuroinflammation; Resatorvid (TAK-242); Toll-like receptor 4 (TLR4); Traumatic brain injury (TBI)