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Chem Biol DOI:10.1016/j.chembiol.2015.03.014

Hydroxamate-based histone deacetylase inhibitors can protect neurons from oxidative stress via a histone deacetylase-independent catalase-like mechanism.

Publication TypeJournal Article
Year of Publication2015
AuthorsOlson, DE, Sleiman, SF, Bourassa, MW, Wagner, FF, Gale, JP, Zhang, Y-L, Ratan, RR, Holson, EB
JournalChem Biol
Volume22
Issue4
Pages439-445
Date Published2015 Apr 23
ISSN1879-1301
KeywordsAnimals, Catalase, Coordination Complexes, Histone Deacetylase Inhibitors, Histone Deacetylases, Hydrogen Peroxide, Hydroxamic Acids, Iron, Mice, Neurons, Neuroprotective Agents, Oxidative Stress, Protein Binding, Reactive Oxygen Species
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1074-5521(15)00107-6
DOI10.1016/j.chembiol.2015.03.014
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25892200?dopt=Abstract

Alternate JournalChem. Biol.
PubMed ID25892200
PubMed Central IDPMC4562013
Grant ListP01 AG014930 / AG / NIA NIH HHS / United States