title: Hydroxamate-based histone deacetylase inhibitors can protect neurons from oxidative stress via a histone deacetylase-independent catalase-like mechanism.
abstract: Histone deacetylase (HDAC) inhibitors have shown enormous promise for treating various disease states, presumably due to their ability to modulate acetylation of histone and non-histone proteins. Many of these inhibitors contain functional groups capable of strongly chelating metal ions. We demonstrate that several members of one such class of compounds, the hydroxamate-based HDAC inhibitors, can protect neurons from oxidative stress via an HDAC-independent mechanism. This previously unappreciated antioxidant mechanism involves the in situ formation of hydroxamate-iron complexes that catalyze the decomposition of hydrogen peroxide in a manner reminiscent of catalase. We demonstrate that while many hydroxamate-containing HDAC inhibitors display a propensity for binding iron, only a subset form active catalase mimetics capable of protecting neurons from exogenous H2O2. In addition to their impact on stroke and neurodegenerative disease research, these results highlight the possibility that HDAC-independent factors might play a role in the therapeutic effects of hydroxamate-based HDAC inhibitors.
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: dolson@broadinstitute.org.
authors.forename: David E
authors.initials: DE
authors.lastname: Olson
authors.affiliation: Department of Natural Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon.
authors.forename: Sama F
authors.initials: SF
authors.lastname: Sleiman
authors.affiliation: Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Megan W
authors.initials: MW
authors.lastname: Bourassa
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Gale
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Burke Medical Research Institute, White Plains, NY 10605, USA; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: edholson@broadinstitute.org.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000633:toxicity; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D007501:Iron / Q000737:chemistry; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism
chemical_list: D056831:Coordination Complexes; C045076:Fenton's reagent; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D007501:Iron; D002374:Catalase; D006655:Histone Deacetylases