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Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

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  • Jinwei Zhang

    (Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories
    Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University)

  • Mohammad Iqbal H. Bhuiyan

    (University of Pittsburgh)

  • Ting Zhang

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Jason K. Karimy

    (Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine)

  • Zhijuan Wu

    (Newcastle University Business School, Newcastle University)

  • Victoria M. Fiesler

    (University of Pittsburgh)

  • Jingfang Zhang

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Huachen Huang

    (University of Pittsburgh)

  • Md Nabiul Hasan

    (University of Pittsburgh)

  • Anna E. Skrzypiec

    (Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories)

  • Mariusz Mucha

    (Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories)

  • Daniel Duran

    (Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine)

  • Wei Huang

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

  • Robert Pawlak

    (Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories)

  • Lesley M. Foley

    (Animal Imaging Center, University of Pittsburgh)

  • T. Kevin Hitchens

    (Animal Imaging Center, University of Pittsburgh
    University of Pittsburgh)

  • Margaret B. Minnigh

    (School of Pharmacy, University of Pittsburgh)

  • Samuel M. Poloyac

    (School of Pharmacy, University of Pittsburgh)

  • Seth L. Alper

    (Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Bradley J. Molyneaux

    (University of Pittsburgh
    University of Pittsburgh)

  • Andrew J. Trevelyan

    (Institute of Neuroscience, Medical School, Newcastle University, Framlington Place)

  • Kristopher T. Kahle

    (Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine)

  • Dandan Sun

    (University of Pittsburgh
    Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center)

  • Xianming Deng

    (State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University)

Abstract

The SLC12A cation-Cl− cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide (“ZT-1a”). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.

Suggested Citation

  • Jinwei Zhang & Mohammad Iqbal H. Bhuiyan & Ting Zhang & Jason K. Karimy & Zhijuan Wu & Victoria M. Fiesler & Jingfang Zhang & Huachen Huang & Md Nabiul Hasan & Anna E. Skrzypiec & Mariusz Mucha & Dani, 2020. "Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13851-6
    DOI: 10.1038/s41467-019-13851-6
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    Cited by:

    1. Enrico Pracucci & Robert T. Graham & Laura Alberio & Gabriele Nardi & Olga Cozzolino & Vinoshene Pillai & Giacomo Pasquini & Luciano Saieva & Darren Walsh & Silvia Landi & Jinwei Zhang & Andrew J. Tre, 2023. "Daily rhythm in cortical chloride homeostasis underpins functional changes in visual cortex excitability," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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