title: Valproic acid prevents NMDA-induced retinal ganglion cell death via stimulation of neuronal TrkB receptor signaling.
abstract: Valproic acid (VPA) is widely prescribed for treatment of epilepsy, mood disorders, migraines, and neuropathic pain. It exerts its therapeutic benefits through multiple mechanisms, including enhancement of GABAergic activity, activation of prosurvival protein kinases, and inhibition of histone deacetylase. Increasing evidence suggests that VPA possesses neuroprotective properties. We examined neuroprotective effects of VPA in an N-methyl-d-aspartate (NMDA) excitotoxicity model, which mimics some of the pathological features of glaucoma. In vivo retinal imaging using optical coherence tomography revealed that NMDA-induced retinal degeneration was suppressed in the VPA-treated retina, and histological analyses confirmed that VPA reduced retinal ganglion cell death. In vivo electrophysiological analyses demonstrated that visual impairment was prevented in the VPA-treated retina, clearly establishing both histological and functional effects of VPA. Brain-derived neurotrophic factor (BDNF) expression was up-regulated in Müller glial cells, and neuroprotective effects of VPA on retinal ganglion cells were significantly reduced in a conditional knockout mouse strain with deletion of tropomyosin receptor kinase B (TrkB), a receptor for BDNF from retinal ganglion cells. The results show that VPA stimulates BDNF up-regulation in Müller glial cells and provides direct evidence that neuronal TrkB is important in VPA-mediated neuroprotection. Also, VPA suppresses oxidative stress induced by NMDA in the retina. Our findings raise intriguing possibilities that the widely prescribed drug VPA may be useful 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: Kazuhiko
authors.initials: K
authors.lastname: Namekata
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: 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: D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020813:Receptor, trkB / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D014635:Valproic Acid; D016202:N-Methylaspartate; D020813:Receptor, trkB