Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury.
Title | Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Shein, N'ama. A., Grigoriadis N., Alexandrovich A. G., Simeonidou C., Lourbopoulos A., Polyzoidou E., Trembovler V., Mascagni P., Dinarello C. A., & Shohami E. |
Journal | FASEB J |
Volume | 23 |
Issue | 12 |
Pagination | 4266-75 |
Date Published | 2009 Dec |
ISSN | 1530-6860 |
Keywords | Animals, Apoptosis, Brain, Brain Injuries, Caspase 3, Histone Deacetylases, Hydroxamic Acids, Male, Mice, Neuroglia, Neuroprotective Agents |
Abstract | 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. |
DOI | 10.1096/fj.09-134700 |
Alternate Journal | FASEB J |
PubMed ID | 19723705 |
PubMed Central ID | PMC2812044 |
Grant List | R01 AI015614 / AI / NIAID NIH HHS / United States R56 AI015614 / AI / NIAID NIH HHS / United States AI-15614 / AI / NIAID NIH HHS / United States |