长期以来，多数神经保护剂研发因临床试验无效或不良反应而中止，直至今年国际卒中大会发布靶向PSD95的多肽NA-1临床III期结果，在临床最常用的溶栓组，由于NA-1会被溶栓剂rt-PA裂解而失效，结果为阴性，但未溶栓组的阳性结果证实PSD95是神经保护剂研发的关键靶点，再次开启药物研究的“大门”。因此，开发靶向PSD95的新型小分子抑制剂，保留神经保护活性而避免被rt-PA裂解，是脑血管病神经保护治疗研发的新策略。预实验发现，靶向全新靶点PSD95-GK的小分子抑制剂，对神经的保护效果优于临床常用药物，可能是潜在新型治疗策略。本项目提出靶向PSD95-GK的小分子抑制剂通过影响缺血再灌注损伤中PSD95蛋白质机器发挥神经保护作用的科学假说，拟从分子、细胞、动物等层面，阐明PSD95-GK小分子抑制剂在缺血性卒中的药理作用及分子机制，为靶向PSD95-GK干预脑卒中新策略的临床应用奠定基础。

The development of most neuroprotectants has been suspended due to negative results of clinical trials or adverse reactions in a long time. Until this year, the International Stroke Conference released the phase III results of peptide NA-1 targeting PSD95 for treatment of ischemic stroke. The results of whole clinical trial were negative, especially in the most commonly used thrombolytic group (rt-PA group), since the NA-1 was decomposed by the thrombolytic agent rt-PA. However, it is exciting that NA-1 showed obvious neuroprotective effect in the group that didn’t use rt-PA. These results indicated PSD95 is the key target for neuroprotectant development and peptide may have some shortcoming when combining with rt-PA. Therefore, the development of new small molecular inhibitors targeting PSD95, which might retain neuroprotective effect but avoid to be decomposed by rt-PA, should be the right strategy for the development of neuroprotective therapy in ischemic stroke. Our preliminary experiments have found that a small molecule inhibitor targeting PSD95-GK domain showed a superior neuroprotective effect than the commonly used clinical drugs, which may be a potential new therapeutic strategy. This project proposes a scientific hypothesis that small molecule inhibitors targeting PSD95-GK should affect the PSD95 protein machinery, thus play a neuroprotective role in ischemia-reperfusion injury. We plan to elucidate the pharmacological action and molecular mechanism of small molecule inhibitors of PSD95-GK in ischemic stroke on the molecular, cellular and animal levels. This study will lay a foundation for the clinical application of the new strategy targeting PSD95-GK for stroke intervention.