title: Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury.
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.
authors.affiliation: Department of Pharmacology, The Hebrew University School of Pharmacy, Jerusalem, Israel.
authors.forename: Na'ama A
authors.initials: NA
authors.lastname: Shein
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Grigoriadis
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Alexandrovich
authors.forename: Constantina
authors.initials: C
authors.lastname: Simeonidou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Lourbopoulos
authors.forename: Eleni
authors.initials: E
authors.lastname: Polyzoidou
authors.forename: Victoria
authors.initials: V
authors.lastname: Trembovler
authors.forename: Paolo
authors.initials: P
authors.lastname: Mascagni
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Esther
authors.initials: E
authors.lastname: Shohami
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology
chemical_list: D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D053148:Caspase 3; D006655:Histone Deacetylases; C502418:givinostat hydrochloride