Hydroxamic acid-based histone deacetylase (HDAC) inhibitors can mediate neuroprotection independent of HDAC inhibition

Sama F. Sleiman, David Olson, Megan W. Bourassa, Saravanan S. Karuppagounder, Yan Ling Zhang, Jennifer Gale, Florence F. Wagner, Manuela Basso, Giovanni Coppola, John T. Pinto, Edward B. Holson, Rajiv R. Ratan

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Histone deacetylase (HDAC) inhibition improves function and extends survival in rodent models of a host of neurological conditions, including stroke, and neurodegenerative diseases. Our understanding, however, of the contribution of individual HDAC isoforms to neuronal death is limited. In this study, we used selective chemical probes to assess the individual roles of the Class I HDAC isoforms in protecting Mus musculus primary cortical neurons from oxidative death.Wedemonstrated that the selectiveHDAC8inhibitor PCI-34051 is a potent neuroprotective agent; and by taking advantage of both pharmacological and genetic tools, we established that HDAC8 is not critically involved in PCI-34051’s mechanism of action.Weused BRD3811, an inactive ortholog of PCI-34051, and showed that, despite its inability to inhibit HDAC8, it exhibits robust neuroprotective properties. Furthermore, molecular deletion of HDAC8 proved insufficient to protect neurons from oxidative death, whereas both PCI-34051 and BRD3811 were able to protect neurons derived from HDAC8 knock-out mice. Finally, we designed and synthesized two new, orthogonal negative control compounds, BRD9715 and BRD8461, which lack the hydroxamic acid motif and showed that they stably penetrate cell membranes but are not neuroprotective. These results indicate that the protective effects of these hydroxamic acid-containing small molecules are likely unrelated to direct epigenetic regulation via HDAC inhibition, but rather due to their ability to bind metals. Our results suggest that hydroxamic acid-based HDAC inhibitors may mediate neuroprotection via HDAC-independent mechanisms and affirm the need for careful structure–activity relationship studies when using pharmacological approaches.

Original languageEnglish (US)
Pages (from-to)14328-14337
Number of pages10
JournalJournal of Neuroscience
Volume34
Issue number43
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Keywords

  • HDAC inhibitors
  • HDAC8
  • Hydroxamic acids
  • Neuroprotection
  • Oxidative stress
  • PCI-34051

ASJC Scopus subject areas

  • Neuroscience(all)

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    Sleiman, S. F., Olson, D., Bourassa, M. W., Karuppagounder, S. S., Zhang, Y. L., Gale, J., Wagner, F. F., Basso, M., Coppola, G., Pinto, J. T., Holson, E. B., & Ratan, R. R. (2014). Hydroxamic acid-based histone deacetylase (HDAC) inhibitors can mediate neuroprotection independent of HDAC inhibition. Journal of Neuroscience, 34(43), 14328-14337. https://doi.org/10.1523/JNEUROSCI.1010-14.2014