title: Valproic acid and ASK1 deficiency ameliorate optic neuritis and neurodegeneration in an animal model of multiple sclerosis.
abstract: Optic neuritis, which is an acute inflammatory demyelinating syndrome of the central nervous system, is one of the major complications in multiple sclerosis (MS). Herein, we investigated the therapeutic potential of valproic acid (VPA) on optic neuritis in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. EAE was induced in C57BL/6 mice by immunization with MOG35-55and VPA (300mg/kg) was administered via intraperitoneal injection once daily from day 3 postimmunization until the end of the experimental period (day 28). VPA treatment suppressed neuroinflammation and decreased the clinical score of EAE at an early phase (from day 12-14 after immunization). We also examined the effects of apoptosis signal-regulating kinase 1 (ASK1), an evolutionarily conserved signaling intermediate for innate immunity, in EAE mice. ASK1 deficiency strongly suppressed microglial activation and decreased the clinical score of EAE at a late phase (day 25, 27 and 28 after immunization). When VPA was administered to ASK1-deficient EAE mice, the clinical score was suppressed in both early and late phases (from day 12-28 after immunization) and showed synergistic effects on protection of retinal neurons. Our findings raise intriguing possibilities that the widely prescribed drug VPA and ASK1 inhibition may be useful for neuroinflammatory disorders including optic neuritis and MS.
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Environmental Science, Graduate School of Science, Toho University, Chiba, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Azuchi
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Guo
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Akiyama
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Noro
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Harada
authors.affiliation: Department of Environmental Science, Graduate School of Science, Toho University, Chiba, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nishigaki
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Environmental Science, Graduate School of Science, Toho University, Chiba, Japan. Electronic address: namekata-kz@igakuken.or.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Namekata
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Harada
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D005260:Female; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009902:Optic Neuritis / Q000188:drug therapy*; D012165:Retinal Ganglion Cells / Q000187:drug effects; D055351:Retinal Neurons / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D014635:Valproic Acid; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: ASK1; EAE; Neuroprotection; Optic neuritis; Valproic acid