title: Valproic acid prevents retinal degeneration in a murine model of normal tension glaucoma.
abstract: Valproic acid (VPA) is widely used for treatment of epilepsy, mood disorders, migraines and neuropathic pain. It exerts its therapeutic benefits through modulation of multiple mechanisms including regulation of gamma-aminobutyric acid and glutamate neurotransmissions, activation of pro-survival protein kinases and inhibition of histone deacetylase. The evidence for neuroprotective properties associated with VPA is emerging. Herein, we investigated the therapeutic potential of VPA in a mouse model of normal tension glaucoma (NTG). Mice with glutamate/aspartate transporter gene deletion (GLAST KO mice) demonstrate progressive retinal ganglion cell (RGC) loss and optic nerve degeneration without elevated intraocular pressure, and exhibit glaucomatous pathology including glutamate neurotoxicity and oxidative stress in the retina. VPA (300mg/kg) or vehicle (PBS) was administered via intraperitoneal injection in GLAST KO mice daily for 2 weeks from the age of 3 weeks, which coincides with the onset of glaucomatous retinal degeneration. Following completion of the treatment period, the vehicle-treated GLAST KO mouse retina showed significant RGC death. Meanwhile, VPA treatment prevented RGC death and thinning of the inner retinal layer in GLAST KO mice. In addition, in vivo electrophysiological analyses demonstrated that visual impairment observed in vehicle-treated GLAST KO mice was ameliorated with VPA treatment, clearly establishing that VPA beneficially affects both histological and functional aspects of the glaucomatous retina. We found that VPA reduces oxidative stress induced in the GLAST KO retina and stimulates the cell survival signalling pathway associated with extracellular-signal-regulated kinases (ERK). This is the first study to report the neuroprotective effects of VPA in an animal model of NTG. Our findings raise intriguing possibilities that the widely prescribed drug VPA may be a novel candidate for treatment of glaucoma.
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: 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: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Namekata
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address: harada-tk@igakuken.or.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Harada
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000235:genetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005901:Glaucoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D014635:Valproic Acid / Q000627:therapeutic use*; D014785:Vision, Ocular / Q000187:drug effects
chemical_list: D027322:Amino Acid Transport System X-AG; D018696:Neuroprotective Agents; D014635:Valproic Acid
keywords: ERK; GLAST KO mice; Neuroprotection; Normal tension glaucoma; Oxidative stress; Valproic acid