Qiang Shao-Jia, Shi Yu-Qi, Wu Tong-Yu, Wang Jing-Quan, Chen Xue-Lian, Su Jie, Chen Xin-Ping, Li Jia-Zhong, Chen Zhe-Sheng
School of Pharmacy, Lanzhou University, Lanzhou, China.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.
Front Pharmacol. 2022 Mar 21;13:877706. doi: 10.3389/fphar.2022.877706. eCollection 2022.
Stroke is the second leading cause of death worldwide and the leading cause of long-term disability that seriously endangers health and quality of human life. Tissue-type fibrinogen activator is currently the only drug approved by FDA for the treatment of ischemic stroke. Neuroprotection is theoretically a common strategy for the treatment of both ischemic and hemorrhagic stroke; therefore, the development of neuroprotective agent has been the focus of research. However, no ideal neuroprotective drug is clinically available. Phosphoglycerate kinase-1 (PGK1) activator has the effect of inhibiting apoptosis and protecting tissue damage, and therefore could be a potential neuroprotective agent. To obtain effective PGK1 activators, we virtually screened a large chemical database and their evaluated the efficacy by the oxidative stress model, PGK1 enzymatic activity assay, and oxygen-glucose stripping reperfusion (OGD/R) model. The results showed that compounds 7979989, Z112553128 and AK-693/21087020 are potential PGK1 activators with protective effects against PQ-induced oxidative stress in the model and could effectively ameliorate apoptosis induced by OGD/R-induced neuronal cell injury. Additionally, compounds 7979989 and Z112553128 are effective in alleviating LPS-induced cellular inflammation. This study indicated that these compounds are promising lead compounds that provide theoretical and material basis to the neuroprotective drug discovery.
中风是全球第二大致死原因，也是导致长期残疾的主要原因，严重危及人类健康和生活质量。组织型纤维蛋白原激活剂是目前美国食品药品监督管理局（FDA）批准的唯一用于治疗缺血性中风的药物。理论上，神经保护是治疗缺血性和出血性中风的常用策略；因此，神经保护剂的研发一直是研究的重点。然而，临床上尚无理想的神经保护药物。磷酸甘油酸激酶-1（PGK1）激活剂具有抑制细胞凋亡和保护组织损伤的作用，因此可能是一种潜在的神经保护剂。为了获得有效的PGK1激活剂，我们对一个大型化学数据库进行了虚拟筛选，并通过氧化应激模型、PGK1酶活性测定和氧糖剥夺再灌注（OGD/R）模型评估了其疗效。结果表明，化合物7979989、Z112553128和AK-693/21087020是潜在的PGK1激活剂，在该模型中对百草枯诱导的氧化应激具有保护作用，并且可以有效改善OGD/R诱导的神经元细胞损伤所导致的细胞凋亡。此外，化合物7979989和Z112553128在减轻脂多糖诱导的细胞炎症方面有效。本研究表明，这些化合物是有前景的先导化合物，为神经保护药物的发现提供了理论和物质基础。
