Selective enhancement of synaptic GABA signaling mediated by GABA-A receptors has been previously reported to promote functional recovery after ischemic stroke, while tonic GABA signaling has been detrimental. To identify agents that enhance synaptic signaling, we synthesized GABA-A ligands based on three chemotypes with affinity values pK_i= 6.44–8.32. Representative compounds showed a preference in functional responses toward synaptic type of GABA-A receptors, compared to the extrasynaptic ones. In a cellular ischemia model (OGD), selected compounds showed the potential to improve neuronal recovery. The selected lead, compound 4, demonstrated the ability to reduce mitochondrial dysfunction, regulate intracellular calcium levels, decrease caspase 3 levels, and promote neurite outgrowth in in vitro assays. In an animal model, compound 4 enhanced motor recovery and showed neuroprotective activity by reducing infarct volume and decreasing poststroke acidosis. These findings underscore the value of selective ligands modulating synaptic GABA-A receptors in promoting recovery from ischemic stroke.

中文翻译：

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优先突触型 GABA-A 受体配体可增强缺血性中风后神经元存活并促进功能恢复


先前已报道 GABA-A 受体介导的突触 GABA 信号传导的选择性增强可促进缺血性中风后的功能恢复，而强直性 GABA 信号传导则是有害的。为了鉴定增强突触信号传导的药物，我们基于亲和力值为 pK= 6.44-8.32 的三种化学型合成了 GABA-A 配体。与突触外 GABA-A 受体相比，代表性化合物对突触型 GABA-A 受体的功能反应表现出偏好。在细胞缺血模型 （OGD） 中，选定的化合物显示出改善神经元恢复的潜力。选定的先导化合物 4 在体外试验中显示出减少线粒体功能障碍、调节细胞内钙水平、降低半胱天冬酶 3 水平和促进神经突生长的能力。在动物模型中，化合物 4 通过减少梗死体积和减少中风后酸中毒来增强运动恢复并显示出神经保护活性。这些发现强调了调节突触 GABA-A 受体的选择性配体在促进缺血性中风恢复方面的价值。