Potential Roles of HDAC Inhibitors in Mitigating Ischemia-induced Brain Damage and Facilitating Endogenous Regeneration and Recovery
2013
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.
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