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

  • Nat Commun. 2020 Jan 7;11(1):78. doi: 10.1038/s41467-019-13851-6.
Jinwei Zhang  1  2 ,  Mohammad Iqbal H Bhuiyan  3 ,  Ting Zhang  4 ,  Jason K Karimy  5 ,  Zhijuan Wu  6 ,  Victoria M Fiesler  3 ,  Jingfang Zhang  4 ,  Huachen Huang  3 ,  Md Nabiul Hasan  3 ,  Anna E Skrzypiec  7 ,  Mariusz Mucha  7 ,  Daniel Duran  5 ,  Wei Huang  4 ,  Robert Pawlak  7 ,  Lesley M Foley  8 ,  T Kevin Hitchens  8  9 ,  Margaret B Minnigh  10 ,  Samuel M Poloyac  10 ,  Seth L Alper  11 ,  Bradley J Molyneaux  3  12 ,  Andrew J Trevelyan  13 ,  Kristopher T Kahle  14 ,  Dandan Sun  15  16 ,  Xianming Deng  17
Affiliations
  • 1. Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK. [email protected].
  • 2. Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, China. [email protected].
  • 3. Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • 4. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 5. Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, 06511, USA.
  • 6. Newcastle University Business School, Newcastle University, Newcastle upon Tyne, NE1 4SE, UK.
  • 7. Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK.
  • 8. Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA, 15203, USA.
  • 9. Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • 10. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • 11. Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
  • 12. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • 13. Institute of Neuroscience, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
  • 14. Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology; Interdepartmental Neuroscience Program; and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, 06511, USA. [email protected].
  • 15. Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA. [email protected].
  • 16. Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA, 15213, USA. [email protected].
  • 17. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. [email protected].
PMID: 31911626 DOI: 10.1038/s41467-019-13851-6
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.

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