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

  • Irina N. Gaisina
    Irina N. Gaisina
    College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
  • Sue H. Lee
    Sue H. Lee
    College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    More by Sue H. Lee
  • Navneet A. Kaidery
    Navneet A. Kaidery
    Department of Pharmacology, Toxicology & Neurology, Augusta University, 1459 Laney Walker Blvd, Augusta, Georgia 30912, United States
  • Manel Ben Aissa
    Manel Ben Aissa
    College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
  • Manuj Ahuja
    Manuj Ahuja
    Department of Pharmacology, Toxicology & Neurology, Augusta University, 1459 Laney Walker Blvd, Augusta, Georgia 30912, United States
    More by Manuj Ahuja
  • Natalya N. Smirnova
    Natalya N. Smirnova
    D. Rogachev Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Samora Mashela 1, Moscow 117997, Russian Federation
  • Sushama Wakade
    Sushama Wakade
    Department of Pharmacology, Toxicology & Neurology, Augusta University, 1459 Laney Walker Blvd, Augusta, Georgia 30912, United States
  • Arsen Gaisin
    Arsen Gaisin
    Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
    More by Arsen Gaisin
  • Megan W. Bourassa
    Megan W. Bourassa
    Feil Family Brain and Mind Research Institute, Weill Medical College at Cornell University, New York, New York 10065, United States
    Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, United States
  • Rajiv R. Ratan
    Rajiv R. Ratan
    Feil Family Brain and Mind Research Institute, Weill Medical College at Cornell University, New York, New York 10065, United States
    Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, United States
  • Sergey V. Nikulin
    Sergey V. Nikulin
    D. Rogachev Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Samora Mashela 1, Moscow 117997, Russian Federation
  • Andrey A. Poloznikov
    Andrey A. Poloznikov
    D. Rogachev Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Samora Mashela 1, Moscow 117997, Russian Federation
  • Bobby Thomas
    Bobby Thomas
    Department of Pharmacology, Toxicology & Neurology, Augusta University, 1459 Laney Walker Blvd, Augusta, Georgia 30912, United States
    More by Bobby Thomas
  • Gregory R. J. Thatcher*
    Gregory R. J. Thatcher
    College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    *(G.R.J.T.) Telephone:+1-312-355-5282. Fax: +1-312-996-7107. E-mail: [email protected]
  • , and 
  • Irina G. Gazaryan*
    Irina G. Gazaryan
    D. Rogachev Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology, Samora Mashela 1, Moscow 117997, Russian Federation
    Feil Family Brain and Mind Research Institute, Weill Medical College at Cornell University, New York, New York 10065, United States
    Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, United States
    Department of Cell Biology and Anatomy, School of Medicine, New York Medical College, 15 Dana Road, Valhalla, New York 10595, United States
    *(I.G.G.) Telephone/Fax: +1-914-773-3774. E-mail: [email protected]
Cite this: ACS Chem. Neurosci. 2018, 9, 5, 894–900
Publication Date (Web):January 17, 2018
https://doi.org/10.1021/acschemneuro.7b00435
Copyright © 2018 American Chemical Society

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    Abstract

    Abstract Image

    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.

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    This article is cited by 22 publications.

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