Activation
of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection
Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors
Posted on 2018-01-17 - 03:13
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.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Gaisina, Irina
N.; Lee, Sue H.; Kaidery, Navneet A.; Ben Aissa, Manel; Ahuja, Manuj; Smirnova, Natalya N.; et al. (2018). Activation
of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection
Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/acschemneuro.7b00435
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
AUTHORS (15)
IG
Irina
N. Gaisina
SL
Sue H. Lee
NK
Navneet A. Kaidery
MB
Manel Ben Aissa
MA
Manuj Ahuja
NS
Natalya N. Smirnova
SW
Sushama Wakade
AG
Arsen Gaisin
MB
Megan W. Bourassa
RR
Rajiv R. Ratan
SN
Sergey V. Nikulin
AP
Andrey A. Poloznikov
BT
Bobby Thomas
GR
Gregory R. J. Thatcher
IG
Irina G. Gazaryan