Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95
Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95
复制标题
通过破坏缺血诱导的 nNOS 与 PSD-95 的相互作用来治疗脑缺血
DOI：
10.1038/nm.2245
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发表时间：
2010-12-01
期刊：
影响因子：
82.9
通讯作者：
Zhu, Dong-Ya
中科院分区：
文献类型：
--
作者：
Zhou, Li;Li, Fei;Zhu, Dong-Ya
中风是导致成人高死亡率和致残率的主要公共卫生问题。n -甲基- d -天冬氨酸受体（NMDARs）的过度刺激和由此产生的神经元一氧化氮合酶（nNOS）的激活对脑卒中后神经元损伤至关重要，，，，。然而，直接抑制NMDARs或nNOS可引起严重的副作用，因为它们在中枢神经系统中具有关键的生理功能，，，，，。本研究表明脑缺血诱导nNOS与突触后密度蛋白-95 （PSD-95）相互作用。通过过表达nNOS的n端氨基酸残基1-133 （nNOS- n1 - 133）破坏nNOS- psd -95的相互作用，可防止谷氨酸诱导的兴奋性毒性和脑缺血损伤。鉴于nNOS-PSD-95相互作用的机制，我们开发了一系列化合物，并发现了nNOS-PSD-95相互作用的小分子抑制剂ZL006。该药物选择性阻断缺血诱导的nNOS-PSD-95关联，体外具有较强的神经保护活性，可改善大脑中动脉闭塞（MCAO）和再灌注小鼠和大鼠局灶性脑缺血损伤。此外，它很容易穿过血脑屏障，对NMDAR功能、nNOS催化活性和空间记忆没有抑制作用，对攻击行为没有影响。因此，这种新药可能作为一种治疗中风的药物，也许没有严重的副作用。
Stroke is a major public health problem leading to high rates of death and disability in adults,. Excessive stimulation ofN-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation are crucial for neuronal injury after stroke insult,,,,. However, directly inhibiting NMDARs or nNOS can cause severe side effects because they have key physiological functions in the CNS,,,,,. Here we show that cerebral ischemia induces the interaction of nNOS with postsynaptic density protein-95 (PSD-95). Disrupting nNOS–PSD-95 interaction via overexpressing the N-terminal amino acid residues 1–133 of nNOS (nNOS-N1–133) prevented glutamate-induced excitotoxicity and cerebral ischemic damage. Given the mechanism of nNOS–PSD-95 interaction, we developed a series of compounds and discovered a small-molecular inhibitor of the nNOS-PSD-95 interaction, ZL006. This drug blocked the ischemia-induced nNOS–PSD-95 association selectively, had potent neuroprotective activityin vitroand ameliorated focal cerebral ischemic damage in mice and rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Moreover, it readily crossed the blood-brain barrier, did not inhibit NMDAR function, catalytic activity of nNOS or spatial memory, and had no effect on aggressive behaviors. Thus, this new drug may serve as a treatment for stroke, perhaps without major side effects.