title: MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury.
abstract: The administration of pan histone deacetylase (HDAC) inhibitors reduces ischemic damage to the CNS, both in vitro and in animal models of stroke, via mechanisms which we are beginning to understand. The acetylation of p53 is regulated by Class I HDACs and, because p53 appears to play a role in ischemic pathology, the purpose of this study was to discover, using an in vitro white matter ischemia model and an in vivo cerebral ischemia model, if neuroprotection mediated by HDAC inhibition depended on p53 expression. Optic nerves were excised from wild-type and p53-deficient mice, and then subjected to oxygen-glucose deprivation in the presence and absence of a specific inhibitor of Class I HDACs (MS-275, entinostat) while compound action potentials were recorded. Furthermore, transient focal ischemia was imposed on wild-type and p53-deficient mice, which were subsequently treated with MS-275. Interestingly, and in both scenarios, the beneficial effects of MS-275 were most pronounced when p53 was absent. These results suggest that modulation of p53 activity is not responsible for MS-275-mediated neuroprotection, and further illustrate how HDAC inhibitors variably influence p53 and associated apoptotic pathways. Optic nerves from wild-type and p53-deficient mice, engineered to express cyan fluorescent protein (CFP) in neuronal mitochondria, were subjected to oxygen-glucose deprivation (OGD) in the presence and absence of a specific inhibitor of Class I histone deacetylases. The protective effect of MS-275 was evidenced by mitochondrial preservation, and this was most pronounced in the absence of p53.
authors.affiliation: Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Murphy
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Megan E
authors.initials: ME
authors.lastname: McClean
authors.forename: Heather E
authors.initials: HE
authors.lastname: Pemberton
authors.forename: Takuma
authors.initials: T
authors.lastname: Uo
authors.forename: Richard S
authors.initials: RS
authors.lastname: Morrison
authors.forename: Chinthasagar
authors.initials: C
authors.lastname: Bastian
authors.forename: Selva
authors.initials: S
authors.lastname: Baltan
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; C118739:entinostat; D006655:Histone Deacetylases
keywords: MS-275; histone deacetylase; ischemia; mouse optic nerve; neuroprotection; p53