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Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury

Na'ama A. Shein^*, Nikolaos Grigoriadis, Alexander G. Alexandrovich^*, Constantina Simeonidou, Athanasios Lourbopoulos, Eleni Polyzoidou, Victoria Trembovler^*, Paolo Mascagni, Charles A. Dinarello^|| and Esther Shohami^*,1

^* Department of Pharmacology, Hebrew University School of Pharmacy, Jerusalem, Israel;

Department of Neurology, AHEPA University Hospital and Aristotle University, Thessaloniki, Greece;

Department of Physiology, Aristotle University, Thessaloniki, Greece;

Center for Research, Balsamo, Italy; and

^|| Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA

¹ Correspondence: Department of Pharmacology, The Hebrew University School of Pharmacy, Jerusalem, Israel 91120. E-mail: esty{at}cc.huji.ac.il

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; P0.05), and that this functional benefit is accompanied by decreased neuronal degeneration, reduced lesion volume (22% reduction vs. vehicle; P0.01), 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.—Shein, N. A., Grigoriadis, N., Alexandrovich, A. G., Simeonidou, C., Lourbopoulos, A., Polyzoidou, E., Trembovler, V., Mascagni, P., Dinarello, C. A., Shohami, E. Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury.

Key Words: epigenetic • closed head injury • regeneration

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