title: TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice.
abstract: Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.
authors.affiliation: 1] Department of Neurology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, China [2] Institute of Neurological Diseases of Xuzhou Medical College, Xuzhou, China [3] Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Prunty
authors.affiliation: University of Georgia, Franklin School of Arts and Sciences, Athens, Georgia, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Hua
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.affiliation: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: D018696:Neuroprotective Agents; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate