Abstract
We compare the ability of two structurally different classes of epigenetic modulators, namely, histone deacetylase (HDAC) inhibitors containing either a hydroxamate or a mercaptoacetamide as the zinc binding group, to protect cortical neurons in culture from oxidative stress-induced death. This study reveals that some of the mercaptoacetamide-based HDAC inhibitors are fully protective, whereas the hydroxamates show toxicity at higher concentrations. Our present results appear to be consistent with the possibility that the mercaptoacetamide-based HDAC inhibitors interact with a different subset of the HDAC isozymes [less activity at HDAC1 and 2 correlates with less inhibitor toxicity], or alternatively, are interacting selectively with only the cytoplasmic HDACs that are crucial for protection from oxidative stress.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / chemistry
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Acetamides / pharmacology
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Acetylation
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Cerebral Cortex / cytology
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Epigenesis, Genetic
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Histone Deacetylase Inhibitors*
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Histone Deacetylases / chemistry
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Histone Deacetylases / genetics
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Histones / metabolism
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Isoenzymes / genetics
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Neurons / cytology
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Neurons / drug effects*
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Neurons / metabolism
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Oxidative Stress / drug effects
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Sulfhydryl Compounds / chemical synthesis*
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Sulfhydryl Compounds / chemistry
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Sulfhydryl Compounds / pharmacology
Substances
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Acetamides
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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Isoenzymes
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Neuroprotective Agents
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Sulfhydryl Compounds
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Histone Deacetylases