Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
Health management center, Shenzhen University general hospital, Shenzhen University clinical medical academy, Shenzhen University Shenzhen, 518060, China.
Toxicol Appl Pharmacol. 2022 Jul 1;446:116055. doi: 10.1016/j.taap.2022.116055. Epub 2022 May 10.
Peroxisome proliferator-activated receptor-gamma (PPARγ) has been shown to have therapeutic promise in the treatment of ischemic stroke and is supported by several studies. To identify possible PPARγ activators, the current study used an in silico technique in conjunction with molecular simulations and in vivo validation. FDA-approved drugs were evaluated using molecular docking to determine their affinity for PPARγ. The findings of molecular simulations support the repurposing of rabeprazole and ethambutol for the treatment of ischemic stroke. Adult Sprague Dawley rats were subjected to transient middle cerebral artery occlusion (t-MCAO). Five groups were made as a sham-operated, t-MCAO group, rabeprazole +t-MCAO, ethambutol +t-MCAO, and pioglitazone +t-MCAO. The neuroprotective effects of these drugs were evaluated using the neurological deficit score and the infarct area. The inflammatory mediators and signaling transduction proteins were quantified using Western blotting, ELISA, and immunohistochemistry. The repurposed drugs mitigated cerebral ischemic injury by PPARγ mediated downregulation of nods like receptor protein 3 inflammasomes (NLRP3), tumor necrosis factor-alpha (TNF-α), cyclooxygenase 2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-kB), and c-Jun N-terminal kinase (p-JNK). Our data demonstrated that rabeprazole and ethambutol have neuroprotective potential via modulating the cytoprotective stress response, increasing cellular survival, and balancing homeostatic processes, and so may be suitable for future research in stroke therapy.
过氧化物酶体增殖物激活受体-γ（PPARγ）在治疗缺血性中风方面显示出治疗潜力，并得到了多项研究的支持。为了鉴定可能的 PPARγ 激动剂，本研究结合分子模拟和体内验证使用了一种计算技术。使用分子对接评估了 FDA 批准的药物，以确定它们与 PPARγ 的亲和力。分子模拟的结果支持将雷贝拉唑和乙胺丁醇重新用于治疗缺血性中风。将成年 Sprague Dawley 大鼠进行短暂性大脑中动脉闭塞（t-MCAO）。分为假手术组、t-MCAO 组、雷贝拉唑+t-MCAO 组、乙胺丁醇+t-MCAO 组和吡格列酮+t-MCAO 组。使用神经功能缺损评分和梗死面积评估这些药物的神经保护作用。使用 Western blot、ELISA 和免疫组织化学定量测定炎症介质和信号转导蛋白。这些重新利用的药物通过 PPARγ 介导的核苷酸结合寡聚化结构域样受体蛋白 3 炎性小体（NLRP3）、肿瘤坏死因子-α（TNF-α）、环氧化酶 2（COX-2）、核因子 kappa-轻链增强子的下调减轻脑缺血损伤B 细胞（p-NF-kB）和 c-Jun N 末端激酶（p-JNK）。我们的数据表明，雷贝拉唑和乙胺丁醇通过调节细胞保护应激反应、增加细胞存活和平衡体内平衡过程具有神经保护潜力，因此可能适合未来的中风治疗研究。
