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

被引：33

作者：

Gaisina, Irina N. ^{[1
]}

Lee, Sue H. ^{[1
]}

Kaidery, Navneet A. ^{[2
]}

Ben Aissa, Manel ^{[1
]}

Ahuja, Manuj ^{[2
]}

Smirnova, Natalya N. ^{[3
]}

Wakade, Sushama ^{[2
]}

Gaisin, Arsen ^{[4
]}

Bourassa, Megan W. ^{[5
,6
]}

Ratan, Rajiv R. ^{[5
,6
]}

Nikulin, Sergey V. ^{[3
]}

Poloznikov, Andrey A. ^{[3
]}

Thomas, Bobby ^{[2
]}

Thatcher, Gregory R. J. ^{[1
]}

Gazaryan, Irina G. ^{[3
,5
,6
,7
]}

机构：

[1] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, 833 South Wood St, Chicago, IL 60612 USA

[2] Augusta Univ, Dept Pharmacol Toxicol & Neurol, 1459 Laney Walker Blvd, Augusta, GA 30912 USA

[3] D Rogachev Fed Sci & Clin Ctr Pediat Hematol Onco, Samora Mashela 1, Moscow 117997, Russia

[4] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, 2145 Sheridan Rd, Evanston, IL 60208 USA

[5] Cornell Univ, Weill Med Coll, Feil Family Brain & Mind Res Inst, New York, NY 10065 USA

[6] Burke Med Res Inst, Sperling Ctr Hemorrhag Stroke Recovery, 785 Mamaroneck Ave, White Plains, NY 10605 USA

[7] New York Med Coll, Sch Med, Dept Cell Biol & Anat, 15 Dana Rd, Valhalla, NY 10595 USA

来源：

ACS CHEMICAL NEUROSCIENCE | 2018年 / 9卷 / 05期

基金：

俄罗斯科学基金会;

关键词：

Phenylhydroxamates; histone deacetylase inhibitors; Nrf2; activators; HIF-1; neuroprotection; oxidative stress; PATHWAY; MECHANISMS; DEFENSE; DISEASE; HIF; THERAPEUTICS; ACETYLATION; ISCHEMIA; PROTECTS; COMPLEX;

D O I：

10.1021/acschemneuro.7b00435

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Activation of HIF-l alpha and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1 alpha 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 reports for HIF-1 alpha 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.

引用

页码：894 / 900

页数：13

共 30 条

[1] Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease [J].