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

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, Daniel Duran, Wei Huang, Robert Pawlak, Lesley M. Foley, T. Kevin Hitchens, Margaret B. Minnigh, Samuel M. Poloyac, Seth L. Alper, Bradley J. Molyneaux, Andrew J. Trevelyan, Kristopher T. Kahle (), Dandan Sun () and Xianming Deng ()
Additional contact information
Jinwei Zhang: Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories
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
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
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
Xianming Deng: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13851-6

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