Dissociation of nNOS from PSD-95 promotes functional recovery after cerebral ischaemia in mice through reducing excessive tonic GABA release from reactive astrocytes
Dissociation of nNOS from PSD-95 promotes functional recovery after cerebral ischaemia in mice through reducing excessive tonic GABA release from reactive astrocytes
复制标题
nNOS 从 PSD-95 解离通过减少反应性星形胶质细胞过度释放 GABA，促进小鼠脑缺血后的功能恢复
DOI：
10.1002/path.4999
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发表时间：
2018-02-01
影响因子：
7.3
通讯作者：
Luo, Chun-Xia
中科院分区：
文献类型：
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作者：
Lin, Yu-Hui;Liang, Hai-Ying;Luo, Chun-Xia
中风后功能恢复的机制尚不清楚，在延迟阶段进行有效的药物干预是可取的。神经元一氧化氮合酶（nNOS）和突触后密度蛋白95 （PSD-95）之间的蛋白-蛋白相互作用是一个潜在的药物靶点，对急性缺血损伤和神经发生至关重要。我们发现，在小鼠光血栓性缺血后第4天至第10天，通过显微注射重组融合蛋白tau - nnos - n1 -133或全身给药小分子ZL006诱导的nNOS-PSD-95解离减少了梗死周围皮层的过度强张性抑制，并改善了运动功能结果。我们还证明了神经可塑性的改善，包括减少nNOS-PSD-95解离引起的过度张力抑制后，树突棘密度和突触发生的增加。脑梗死周围皮层反应性星形胶质细胞中γ -氨基丁酸（GABA）和GABA转运蛋白3/4 （GAT-3/4）水平升高。GAT-3/4选择性拮抗剂SNAP-5114降低了强直性抑制并促进了功能恢复，这表明梗死周围皮层强直性抑制的增加是由于反应性星形胶质细胞中逆转GAT-3/4释放GABA所致。缺血后用Tat-nNOS-N1-133或ZL006治疗可抑制星形胶质细胞的激活和GABA的产生，阻止GAT-3/4的逆转，从而减少过度的强直性抑制并改善功能结果。潜在的分子机制与通过减少NO的产生抑制谷氨酸脱羧酶67和单胺氧化酶B的表观遗传表达有关。因此，nNOS-PSD-95相互作用是脑卒中后功能恢复的潜在靶点，而这种相互作用的小分子抑制剂ZL006是一种很有前途的药理先导化合物。版权所有2017英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
Mechanisms underlying functional recovery after stroke are little known, and effective drug intervention during the delayed stage is desirable. One potential drug target, the protein-protein interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein 95 (PSD-95), is critical to acute ischaemic damage and neurogenesis. We show that nNOS-PSD-95 dissociation induced by microinjection of a recombinant fusion protein, Tat-nNOS-N1-133, or systemic administration of a small-molecule, ZL006, from day 4 to day 10 after photothrombotic ischaemia in mice reduced excessive tonic inhibition in the peri-infarct cortex and ameliorated motor functional outcome. We also demonstrated improved neuroplasticity including increased dendrite spine density and synaptogenesis after reducing excessive tonic inhibition by nNOS-PSD-95 dissociation. Levels of gamma-aminobutyric acid (GABA) and GABA transporter-3/4 (GAT-3/4) are increased in the reactive astrocytes in the peri-infarct cortex. The GAT-3/4-selective antagonist SNAP-5114 reduced tonic inhibition and promoted function recovery, suggesting that increased tonic inhibition in the peri-infarct cortex was due to GABA release from reversed GAT-3/4 in reactive astrocytes. Treatments with Tat-nNOS-N1-133 or ZL006 after ischaemia inhibited astrocyte activation and GABA production, prevented the reversal of GAT-3/4, and consequently decreased excessive tonic inhibition and ameliorated functional outcome. The underlying molecular mechanisms were associated with epigenetic inhibition of glutamic acid decarboxylase 67 and monoamine oxidase B expression through reduced NO production. The nNOS-PSD-95 interaction is thus a potential target for functional restoration after stroke and ZL006, a small molecule inhibitor of this interaction, is a promising pharmacological lead compound. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.