2. Academic Validation
  3. Modulation of brain cation-Cl- cotransport via the SPAK kinase inhibitor ZT-1a

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

Affiliations

  • 1 Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, EX4 4PS, UK. j.zhang5@exeter.ac.uk.
  • 2 Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361004, China. j.zhang5@exeter.ac.uk.
  • 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. kristopher.kahle@yale.edu.
  • 15 Department of Neurology and Pittsburgh Institute For Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA. sund@upmc.edu.
  • 16 Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA, 15213, USA. sund@upmc.edu.
  • 17 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China. xmdeng@xmu.edu.cn.
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z