Potential Roles of HDAC Inhibitors in Mitigating Ischemia-induced Brain Damage and Facilitating Endogenous Regeneration and Recovery

Author(s): Emily B. Fessler , Fairouz L. Chibane , Zhifei Wang , De-Maw Chuang .

Journal Name: Current Pharmaceutical Design

Volume 19 , Issue 28 , 2013

Abstract:

Ischemic stroke is a leading cause of death and disability worldwide, with few available treatment options. The pathophysiology of cerebral ischemia involves both early phase tissue damage, characterized by neuronal death, inflammation, and blood-brain barrier breakdown, followed by late phase neurovascular recovery. It is becoming clear that any promising treatment strategy must target multiple points in the evolution of ischemic injury to provide substantial therapeutic benefit. Histone deacetylase (HDAC) inhibitors are a class of drugs that increase the acetylation of histone and non-histone proteins to activate transcription, enhance gene expression, and modify the function of target proteins. Acetylation homeostasis is often disrupted in neurological conditions, and accumulating evidence suggests that HDAC inhibitors have robust protective properties in many preclinical models of these disorders, including ischemic stroke. Specifically, HDAC inhibitors such as trichostatin A, valproic acid, sodium butyrate, sodium 4-phenylbutyrate, and suberoylanilide hydroxamic acid have been shown to provide robust protection against excitotoxicity, oxidative stress, ER stress, apoptosis, inflammation, and bloodbrain barrier breakdown. Concurrently, these agents can also promote angiogenesis, neurogenesis and stem cell migration to dramatically reduce infarct volume and improve functional recovery after experimental cerebral ischemia. In the following review, we discuss the mechanisms by which HDAC inhibitors exert these protective effects and provide evidence for their strong potential to ultimately improve stroke outcome in patients.

Keywords: Histone deacetylase inhibitors, ischemia, stroke, neuroprotection, anti-inflammation, angiogenesis, neurogenesis, functional recovery.

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Article Details

VOLUME: 19
ISSUE: 28
Year: 2013
Page: [5105 - 5120]
Pages: 16
DOI: 10.2174/1381612811319280009
Price: $58

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