Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors

Irina N. Gaisina, Sue H. Lee, Navneet A. Kaidery, Manel Ben Aissa, Manuj Ahuja, Natalya N. Smirnova, Sushama Wakade, Arsen Gaisin, Megan W. Bourassa, Rajiv R. Ratan, Sergey V. Nikulin, Andrey A. Poloznikov, Bobby Thomas, Gregory R.J. Thatcher, Irina G. Gazaryan

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.

Original languageEnglish (US)
Pages (from-to)894-900
Number of pages7
JournalACS Chemical Neuroscience
Volume9
Issue number5
DOIs
StatePublished - May 16 2018

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Keywords

  • HIF-1 activators
  • Nrf2 activators
  • Phenylhydroxamates
  • histone deacetylase inhibitors
  • neuroprotection
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Gaisina, I. N., Lee, S. H., Kaidery, N. A., Ben Aissa, M., Ahuja, M., Smirnova, N. N., Wakade, S., Gaisin, A., Bourassa, M. W., Ratan, R. R., Nikulin, S. V., Poloznikov, A. A., Thomas, B., Thatcher, G. R. J., & Gazaryan, I. G. (2018). Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors. ACS Chemical Neuroscience, 9(5), 894-900. https://doi.org/10.1021/acschemneuro.7b00435