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Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors
journal contribution
posted on 2018-01-17, 03:13 authored by 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. GazaryanActivation
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.