Valproic acid and ASK1 deficiency ameliorate optic neuritis and neurodegeneration in an animal model of multiple sclerosis.
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 MOG35-55 and 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.
['Azuchi|Yuriko|Y|', 'Kimura|Atsuko|A|', 'Guo|Xiaoli|X|', 'Akiyama|Goichi|G|', 'Noro|Takahiko|T|', 'Harada|Chikako|C|', 'Nishigaki|Atsuko|A|', 'Namekata|Kazuhiko|K|', 'Harada|Takayuki|T|']
D000818:Animals D004195:Disease Models, Animal D004681:Encephalomyelitis, Autoimmune, Experimental D005260:Female D048848:MAP Kinase Kinase Kinase 5 D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009103:Multiple Sclerosis D009902:Optic Neuritis D012165:Retinal Ganglion Cells D055351:Retinal Neurons D014635:Valproic Acid
Valproic acid ASK1 Optic neuritis EAE Neuroprotection