title: Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery.
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.
authors: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Dr, MSC 1363, Bethesda, MD 20892-1363, USA.
authors: Emily B
authors: EB
authors: Fessler
authors: Fairouz L
authors: FL
authors: Chibane
authors: Zhifei
authors: Z
authors: Wang
authors: De-Maw
authors: DM
authors: Chuang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002552:Cerebral Ventricles / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects*; D015427:Reperfusion Injury / Q000517:prevention & control*; D020521:Stroke / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents