PMID- 25542970
OWN - NLM
STAT- MEDLINE
DCOM- 20151125
LR  - 20150223
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 185
IP  - 3
DP  - 2015 Mar
TI  - Valproic acid prevents NMDA-induced retinal ganglion cell death via stimulation 
      of neuronal TrkB receptor signaling.
PG  - 756-64
LID - S0002-9440(14)00673-7 [pii]
LID - 10.1016/j.ajpath.2014.11.005 [doi]
AB  - 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 Muller 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 Muller 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.
CI  - Copyright (c) 2015 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Kimura, Atsuko
AU  - Kimura A
AD  - Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 
      Japan.
FAU - Namekata, Kazuhiko
AU  - Namekata K
AD  - Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 
      Japan.
FAU - Guo, Xiaoli
AU  - Guo X
AD  - Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 
      Japan.
FAU - Noro, Takahiko
AU  - Noro T
AD  - Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 
      Japan.
FAU - Harada, Chikako
AU  - Harada C
AD  - Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 
      Japan.
FAU - Harada, Takayuki
AU  - Harada T
AD  - Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 
      Japan. Electronic address: harada-tk@igakuken.or.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141224
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Neuroprotective Agents)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Cell Death/*drug effects
MH  - Mice
MH  - N-Methylaspartate/*pharmacology
MH  - Neuroprotective Agents/*pharmacology
MH  - Receptor, trkB/*metabolism
MH  - Retinal Ganglion Cells/*drug effects/metabolism/pathology
MH  - Signal Transduction/*drug effects
MH  - Up-Regulation/drug effects
MH  - Valproic Acid/*pharmacology
EDAT- 2014/12/30 06:00
MHDA- 2015/12/15 06:00
CRDT- 2014/12/28 06:00
PHST- 2014/10/03 00:00 [received]
PHST- 2014/11/04 00:00 [revised]
PHST- 2014/11/10 00:00 [accepted]
PHST- 2014/12/28 06:00 [entrez]
PHST- 2014/12/30 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - S0002-9440(14)00673-7 [pii]
AID - 10.1016/j.ajpath.2014.11.005 [doi]
PST - ppublish
SO  - Am J Pathol. 2015 Mar;185(3):756-64. doi: 10.1016/j.ajpath.2014.11.005. Epub 2014 
      Dec 24.