Abstract
Histone deacetylase (HDAC) inhibitors are emerging as a novel class of potentially therapeutic agents for treating acute injuries of the central nervous system (CNS). In this review, we summarize data regarding the effects of HDAC inhibitor administration in models of acute CNS injury and discuss issues warranting clinical trials. We have previously shown that the pan-HDAC inhibitor ITF2357, a compound shown to be safe and effective in humans, improves functional recovery and attenuates tissue damage when administered as late as 24 h after injury. Using a well-characterized, clinically relevant mouse model of closed head injury, we demonstrated that a single dose of ITF2357 administered 24 h after injury improves neurobehavioral recovery and reduces tissue damage. ITF2357-induced functional improvement was found to be sustained up to 14 d after trauma and was associated with augmented histone acetylation. Single postinjury administration of ITF2357 also attenuated injury-induced inflammatory responses, as indicated by reduced glial accumulation and activation as well as enhanced caspase-3 expression within microglia/macrophages after treatment. Because no specific therapeutic intervention is currently available for treating brain trauma patients, the ability to affect functional outcome by postinjury administration of HDAC inhibitors within a clinically feasible timeframe may be of great importance. Furthermore, a growing body of evidence indicates that HDAC inhibitors are beneficial for treating various forms of acute CNS injury including ischemic and hemorrhagic stroke. Because HDAC inhibitors are currently approved for other use, they represent a promising new avenue of treatment, and their use in the setting of CNS injury warrants clinical evaluation.
Highlights
Acute central nervous system (CNS)injury is a major cause of prolonged morbidity and mortality in the adult population
Rather than a quantitative surge, the tilt in acetylation homeostasis does not involve an increase in Histone deacetylase (HDAC) quantity or activity; it is due to the loss of balance stemming from reduced histone acetylase transferase (HAT) activity
The wide-ranging neuroprotective potential indicated by this work, taken together with the fact that several HDAC inhibitors were already used clinically for other indications including epilepsy, sickle cell anemia and T-cell lymphoma [39,40,41], and the vital need for developing new therapeutics for acute CNS injury, fueled research efforts aimed at evaluating the use of HDAC inhibitors for treating stroke and CNS trauma
Summary
Injury is a major cause of prolonged morbidity and mortality in the adult population. CELLULAR PROTEIN ACETYLATION Under normal conditions, stability of cellular acetylation homeostasis is preserved by maintenance of an appropriate balance between two discrete sets of enzymes that facilitate forward and backward modifications [17,18] These enzymes, HAT and HDAC, have been the focus of extensive research owing to the key role of histones in cellular function and disease [19,20]. Enhanced acetylation induces chromatin remodeling to a loosely packed configuration that enables subsequent gene transcription, whereas increased deacetylation fosters chromatin condensation and reduced gene expression It should be noted, that nonhistone proteins linked to microtubule stability, metabolism and aging have been shown to serve as substrates for certain HDACs [21,22,23,24], highlighting the importance of acetylation as a posttranslational mode of regulation. Class IV consists of a single member, HDAC 11, which shares certain characteristics with class I and class II HDACs, but has been suggested to facilitate different physiological roles [30]
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