Dissociating nNOS (Neuronal NO Synthase)-CAPON (Carboxy-Terminal Postsynaptic Density-95/Discs Large/Zona Occludens-1 Ligand of nNOS) Interaction Promotes Functional Recovery After Stroke via Enhanced Structural Neuroplasticity
Dissociating nNOS (Neuronal NO Synthase)-CAPON (Carboxy-Terminal Postsynaptic Density-95/Discs Large/Zona Occludens-1 Ligand of nNOS) Interaction Promotes Functional Recovery After Stroke via Enhanced Structural Neuroplasticity
复制标题
解离 nNOS（神经元 NO 合成酶）-CAPON（nNOS 的羧基末端突触后密度 - 95/Discs Large/Zona Occlusionns-1 配体）相互作用通过增强的结构神经可塑性促进中风后功能恢复
DOI：
10.1161/strokeaha.118.022647
复制
发表时间：
2019-03-01
期刊：
影响因子：
8.3
通讯作者：
Zhu, Dong-Ya
中科院分区：
文献类型：
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作者：
Ni, Huan-Yu;Song, Yi-Xuan;Zhu, Dong-Ya
背景和目的-脑卒中是全球主要的公共卫生问题。虽然中风后急性期的临床治疗有所改善，但长期治疗仍限于延迟期的身体康复。本研究的目的是确定是否nNOS（神经元NO合酶）-CAPON（羧基末端突触后密度-95/光盘大/nNOS闭塞-1配体）的相互作用可能作为一个新的治疗目标，在延迟阶段中风recovery. Methods-光血栓性中风和短暂的大脑中动脉闭塞诱导小鼠。分别于光血栓性脑卒中后即刻和4 ~ 10天将腺相关病毒（AAV）-巨细胞病毒（CMV）-CAPON-125 C-GFP（绿色荧光蛋白）-3 Flag和其他2种药物（Tat-CAPON-12 C和ZLc-002）显微注射到梗死周围皮层。ZLc-002也在短暂性大脑中动脉闭塞后4至10天全身注射。采用网格行走任务和圆柱任务评估运动功能。Western blotting，免疫组化，高尔基体染色，和电生理记录进行揭示的mechanism.Results-Stroke增加nNOS-CAPON协会在梗死周围皮层的延迟期。抑制缺血诱导的nNOS-CAPON协会大幅减少了在网格行走任务和前肢不对称的圆柱体任务中的足部故障的数量，这表明促进中风的功能恢复。此外，解离nNOS-CAPON显着促进树突重塑和突触传递，增加树突棘密度，树突分支，长度和微型兴奋性突触后电流频率，但不影响中风引起的神经元丢失，梗死面积，或脑水肿，表明nNOS-CAPON相互作用可能通过调节结构神经可塑性，而不是神经保护。此外，ZLc-002逆转了短暂的大脑中动脉闭塞引起的运动functions. Conclusions，我们的研究结果表明，nNOS-CAPON耦合可以作为一个新的药理学目标，中风后的功能恢复。可视概述-本文提供了一个在线可视概述。（中风。2019;50：728-737. DOI：10.1161/STROKEAHA.118.022647。）
Background and Purpose-Stroke is a major public health concern worldwide. Although clinical treatments have improved in the acute period after stroke, long-term therapeutics remain limited to physical rehabilitation in the delayed phase. This study is aimed to determine whether nNOS (neuronal NO synthase)-CAPON (carboxy-terminal postsynaptic density-95/ discs large/zona occludens-1 ligand of nNOS) interaction may serve as a new therapeutic target in the delayed phase for stroke recovery.Methods-Photothrombotic stroke and transient middle cerebral artery occlusion were induced in mice. Adeno-associated virus (AAV)-cytomegalovirus (CMV)-CAPON-125C-GFP (green fluorescent protein)-3Flag and the other 2 drugs (Tat-CAPON-12C and ZLc-002) were microinjected into the peri-infarct cortex immediately and 4 to 10 days after photothrombotic stroke, respectively. ZLc-002 was also systemically injected 4 to 10 days after transient middle cerebral artery occlusion. Grid-walking task and cylinder task were conducted to assess motor function. Western blotting, immunohistochemistry, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms.Results-Stroke increased nNOS-CAPON association in the peri-infarct cortex in the delayed period. Inhibiting the ischemia-induced nNOS-CAPON association substantially decreased the number of foot faults in the grid-walking task and forelimb asymmetry in the cylinder task, suggesting the promotion of functional recovery from stroke. Moreover, dissociating nNOS-CAPON significantly facilitated dendritic remodeling and synaptic transmission, indicated by increased dendritic spine density, dendritic branching, and length and miniature excitatory postsynaptic current frequency but did not affect stroke-elicited neuronal loss, infarct size, or cerebral edema, suggesting that nNOS-CAPON interaction may function via regulating structural neuroplasticity, rather than neuroprotection. Furthermore, ZLc-002 reversed the transient middle cerebral artery occlusion-induced impairment of motor function.Conclusions-Our results reveal that nNOS-CAPON coupling can serve as a novel pharmacological target for functional restoration after stroke. Visual Overview-An online visual overview is available for this article. (Stroke. 2019;50:728-737. DOI: 10.1161/STROKEAHA.118.022647.)