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
复制标题
通过SPAK激酶抑制剂ZT-1a调节脑阳离子-Cl(-)共转运
DOI：
10.1038/s41467-019-13851-6
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发表时间：
2020-01-07
影响因子：
16.6
通讯作者：
Deng, Xianming
中科院分区：
文献类型：
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作者：
Zhang, Jinwei;Bhuiyan, Mohammad Iqbal H.;Deng, Xianming
SLC12A阳离子-氯转运体(CCC)，包括NKCC1和KCCs，是脑内离子稳态的重要决定因素。SPAK激酶(STK39)是CCC的主调控子，它通过保守的共享基序上的磷酸化，刺激NKCC1离子内流，抑制KCC介导的外流。SPAK依赖的CCC磷酸化上调与多种神经系统疾病有关。利用支架-杂交策略，我们开发了一种新的有效和选择性的SPAK抑制剂5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide(“ZT-1a”)。ZT-1a通过减少Spak依赖的磷酸化来抑制NKCC1并刺激KCC。在出血性脑积水模型中，侧脑室内注射ZT-1a可减少炎症诱导的脉络丛中CCC的磷酸化，并减少脑脊液(CSF)的高分泌。在卒中模型中，全身应用ZT-1a可减少缺血诱导的CCC磷酸化，减轻脑水肿，保护大脑免受损伤，并改善预后。这些结果提示ZT-1a或相关化合物可能是有效的CCC调节剂，具有治疗与离子稳态受损相关的脑疾病的潜力。
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.