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

TitleActivation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors.
Publication TypeJournal Article
Year of Publication2018
AuthorsGaisina IN, Lee SH, Kaidery NA, Ben Aissa M, Ahuja M, Smirnova NN, Wakade S, Gaisin A, Bourassa MW, Ratan RR, Nikulin SV, Poloznikov AA, Thomas B, Thatcher GRJ, Gazaryan IG
JournalACS Chem Neurosci
Date Published2018 Jan 17
ISSN1948-7193
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.

DOI10.1021/acschemneuro.7b00435
Alternate JournalACS Chem Neurosci
PubMed ID29338172
Grant ListR01 NS060885 / NS / NINDS NIH HHS / United States
R01 NS101967 / NS / NINDS NIH HHS / United States