Valproic acid increases white matter repair and neurogenesis after stroke.
Acute treatment of stroke with histone deacetylase (HDAC) inhibitors has been shown to reduce ischemic cell damage; however, it is unclear whether delayed treatment with HDAC inhibitors will contribute to the brain repair and plasticity. In the present study, we investigated the effects of delayed treatment of stroke with a pan HDAC inhibitor, valproic acid (VPA), on white matter injury and neurogenesis during stroke recovery. Administration of VPA at a dose of 100mg/kg for 7 days starting 24h after middle cerebral artery occlusion (MCAo) in rats significantly improved neurological outcome measured 7-28 days post-MCAo. In addition, the VPA treatment significantly increased oligodendrocyte survival and newly generated oligodendrocytes, which was associated with elevation of myelinated axonal density in the ischemic boundary 28 days after MCAo. VPA treatment also increased the expression of glutamate transporter 1 (GLT1) in the ischemic boundary after stroke, and increased acetylated histone H4 expression in neuroblasts and the number of new neurons in striatal ischemic boundary region. This study provides new evidence that the delayed VPA treatment enhances white matter repair and neurogenesis in ischemic brain, which may contribute to improved functional outcome.
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA. xsliu@neuro.hfh.edu
X S
XS
Liu
M
M
Chopp
H
H
Kassis
L F
LF
Jia
A
A
Hozeska-Solgot
R L
RL
Zhang
C
C
Chen
Y S
YS
Cui
Z G
ZG
Zhang
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000473:pathology*; D014635:Valproic Acid / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid