title: Histone deacetylase inhibition is cytotoxic to oligodendrocyte precursor cells in vitro and in vivo.
abstract: Histone deacetylase (HDAC) inhibition mediated by small molecule HDAC inhibitors (HDACi) has demonstrated divergent effects including toxicity towards transformed cell lines, neuroprotection in neurological disease models, and inhibition of oligodendrocyte precursor cell (OPC) differentiation to mature oligodendrocytes (OL). However, it remains unknown if transient HDAC inhibition may promote OPC survival. Using mouse cortical OPC primary cultures, we investigated the effects of the FDA approved pan-HDACi suberoylanilide hydroxamic acid (SAHA) on OPC survival. Initial studies showed differences in the HDAC expression pattern of multiple HDAC isoforms in OPCs relative to their terminally differentiated progeny cells, OLs and astrocytes. Treatment of OPCs with SAHA for up to 72h using a maximum concentration either at or lower than those necessary for cytotoxicity in most transformed cell lines resulted in over 67% reduction in viability relative to vehicle-treated OPCs. This was at least partly due to increased apoptosis as SAHA-treated cells displayed activated caspase 3 and were protected by the general caspase inhibitor Q-VD-OPH. Additionally, SAHA treatment of whole mice at postnatal day 5 induced apoptosis of cortical OPCs. These results suggest that SAHA negatively impacts OPC survival and may be detrimental to the myelinating brain and spinal cord. Such toxicity may be relevant in a clinical context as SAHA is currently involved in numerous clinical trials and is in consideration for use in the treatment of psychiatric and neurodegenerative conditions.
authors: Division of Hematology & Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States.
authors: Toros A
authors: TA
authors: Dincman
authors: Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States; Cardiovascular Innovation Institute, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States.
authors: Jason E
authors: JE
authors: Beare
authors: Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States; Departments of Neurological Surgery, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States.
authors: Sujata Saraswat
authors: SS
authors: Ohri
authors: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, United States.
authors: Vittorio
authors: V
authors: Gallo
authors: Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States; Departments of Neurological Surgery, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States; Pharmacology & Toxicology, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States.
authors: Michal
authors: M
authors: Hetman
authors: Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States; Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States; Departments of Neurological Surgery, University of Louisville School of Medicine, 511 South Floyd Street, MDR 616, Louisville, KY 40292, United States. Electronic address: swhittemore@louisville.edu.
authors: Scott R
authors: SR
authors: Whittemore
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000187:drug effects / Q000201:enzymology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D020169:Caspases; D006655:Histone Deacetylases
keywords: Chemotherapy-induced cognitive impairment; Cytotoxicity; Histone deacetylase; Histone deacetylase inhibitor; Oligodendrocyte precursor cell; Suberoylanilide hydroxamic acid