Despite efforts aimed at developing novel
therapeutics for
traumatic brain injury (TBI), no specific pharmacological agent is currently clinically available. Here, we show that the pan-
histone deacetylase (
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 postinjury. Using a well-characterized, clinically relevant mouse model of
closed head injury (CHI), we demonstrate that a single dose of
ITF2357 administered 24 h postinjury improves neurobehavioral recovery from d 6 up to 14 d postinjury (improved neurological score vs. vehicle; P< or =0.05), and that this functional benefit is accompanied by decreased neuronal degeneration, reduced lesion volume (22% reduction vs. vehicle; P< or =0.01), and is preceded by increased acetylated
histone H3 levels and attenuation of injury-induced decreases in cytoprotective
heat-shock protein 70 kDa and phosphorylated Akt. Moreover, reduced glial accumulation and activation were observed 3 d postinjury, and total p53 levels at the area of injury and
caspase-3 immunoreactivity within microglia/macrophages at the
trauma area were elevated, suggesting enhanced clearance of these cells via apoptosis following treatment. Hence, our findings underscore the relevance of
HDAC inhibitors for ameliorating
trauma-induced functional deficits and warrant consideration of applying
ITF2357 for this indication.