title: Toll-like receptor 4 antagonist attenuates intracerebral hemorrhage-induced brain injury.
abstract: OBJECTIVE
  Accumulating evidence indicates that inflammatory responses cause secondary injury after intracerebral hemorrhage (ICH). We recently demonstrated the involvement of toll-like receptor 4 (TLR4) signaling in these processes. The purpose of the current study was to investigate the protective effect and mechanism of TAK-242 (Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1 -carboxylate, Takeda), a TLR4 antagonist, in an ICH mouse model.
  
  
  METHODS
  TAK-242 was intraperitoneally injected 6 hours after ICH once daily for 5 successive days. We assessed neurological deficit scores; changes in brain water content; and levels of inflammatory factors, DNA damage, and neuronal degeneration in perihematomal region 1, 3, and 5 days after ICH. Peripheral inflammatory cell infiltration was determined using flow cytometry; and the expression of TLR4 downstream signaling molecules was assessed by Western blot.
  
  
  RESULTS
  TAK-242 significantly reduced brain water content, neurological deficit scores, and levels of inflammatory factors. The levels of DNA damage and neuronal degeneration were also significantly decreased, as was peripheral inflammatory cell infiltration. The expression of TLR4 downstream signaling molecules, including myeloid differentiation primary response gene 88, toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta IκBα, nuclear factor-κBp65, and phosphorylated nuclear factor-κBp65, was significantly downregulated.
  
  
  CONCLUSIONS
  The results suggest that TLR4 antagonist reduced inflammatory injury and neurological deficits in a mouse model of ICH. The mechanism may involve decreased expression of signaling molecules downstream of TLR4.
authors.affiliation: Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wang
authors.forename: Huang
authors.initials: H
authors.lastname: Fang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiong
authors.forename: Qing-Wu
authors.initials: QW
authors.lastname: Yang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D002543:Cerebral Hemorrhage / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D018836:Inflammation Mediators; 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: NF-κB; ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate; inflammation; intracerebral hemorrhage; toll-like receptor 4