title: Inhibition of Leukotriene B4 Action Mitigates Intracerebral Hemorrhage-Associated Pathological Events in Mice.
abstract: Infiltration of neutrophils has been suggested to play an important role in the pathogenesis of intracerebral hemorrhage (ICH) for which effective therapeutic interventions remain unavailable. In the present study we focused on leukotriene B4(LTB4) as a potent chemotactic factor for neutrophils in order to address its contribution to the pathologic events associated with ICH. ICH with hematoma expansion into the internal capsule that resulted in severe sensorimotor dysfunction was induced by injection of collagenase in mouse striatum. We found that LTB4as well as mRNAs of 5-lipoxygenase (5-LOX) and 5-LOX-activating protein were increased in the brain after ICH. Daily treatment with a 5-LOX inhibitor zileuton (3 or 10 mg/kg, i.v.) prevented ICH-induced increase in LTB4, attenuated neutrophil infiltration into the hematoma, and ameliorated sensorimotor dysfunction. In addition, mice deficient in LTB4receptor BLT1exhibited a lower number of infiltrating neutrophils in the hematoma and lower levels of sensorimotor dysfunction after ICH than did wild-type mice. Similarly, daily treatment of mice with BLT antagonist ONO-4057 (30 or 100 mg/kg, by mouth) from 3 hours after induction of ICH inhibited neutrophil infiltration and ameliorated sensorimotor dysfunction. ONO-4057 also attenuated inflammatory responses of microglia/macrophages in the perihematoma region and axon injury in the internal capsule. These results identify LTB4as a critical factor that plays a major role in the pathogenic events in ICH, and BLT1is proposed as a promising target for ICH therapy.
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Masanori
authors.initials: M
authors.lastname: Hijioka
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Junpei
authors.initials: J
authors.lastname: Anan
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Hayato
authors.initials: H
authors.lastname: Ishibashi
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kurauchi
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Akinori
authors.initials: A
authors.lastname: Hisatsune
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.).
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences (M.H., J.A., H.I., Y.K., T.Se., H.K.), Priority Organization for Innovation and Excellence (A.H., T.K.), and Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Global Oriented) Program" (A.H., T.K.), Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan (T.K., T.Y); Department of Lipid Signaling Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan (T.Sh.); and Department of Lipidomics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.Sh.) hkatsuki@gpo.kumamoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; D016859:Lipoxygenase Inhibitors; D010666:Phenylpropionates; D018102:Receptors, Leukotriene B4; C067523:ONO-LB 457; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea