Chronic valproate treatment enhances post-ischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIMH	PHARM/PHYS-6

* FARE Award Winner

Authors

• Z. Wang
• L.K. Tsai
• J. Munasinghe
• Y. Leng
• E.B. Fessler
• F. Chibane
• P. Leeds
• D.M. Chuang

Abstract

Enhanced angiogenesis facilitates neurovascular remodeling processes and promotes brain functional recovery after stroke. Previous studies demonstrated that valproate (VPA), a histone deacetylase (HDAC) inhibitor, protects against experimental brain ischemia. The present study investigated whether VPA could enhance angiogenesis and promote long-term functional recovery after ischemic stroke. Male rats underwent transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Post-ischemic VPA treatment robustly improved the rotarod performance of MCAO rats on days 7 and 14, and significantly reduced brain infarction on day 14. Concurrently, VPA markedly enhanced microvessel density, facilitated endothelial cell proliferation, and increased relative cerebral blood flow in the ipsilateral cortex. The transcription factor hypoxia-inducible factor (HIF)-1apha and its downstream pro-angiogenic factors, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2/9, were upregulated after MCAO and significantly potentiated by VPA in the ipsilateral cortex. Acetylation of histone-H3 and H4 was robustly increased by chronic VPA treatment. The beneficial effects of VPA on rotarod performance and microvessel density were abolished by HIF-1alpha inhibition. Our findings demonstrate that chronic VPA treatment enhances post-ischemic angiogenesis and promotes functional recovery. These effects may involve HDAC inhibition and upregulation of HIF-1alpha and its downstream pro-angiogenic factors VEGF and MMP-2/9.

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