Discovery of platelet glycoprotein VI receptor antagonists and their neuroprotective activity: an in silico, in vitro, and in vivo study.

IF 2.9 4区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
3 Biotech Pub Date : 2025-10-01 Epub Date: 2025-09-21 DOI:10.1007/s13205-025-04530-z
Mohammad Aquib Siddiqui, Poorvi Saraf, Sushant Kumar Shrivastava, Sudha Madhavi Penumaka, Debabrata Mandal, Ravi Saini, Abhishek Pathak, Kakarla Ramakrishna, Sairam Krishnamurthy
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引用次数: 0

Abstract

The present study utilized a drug repurposing approach to identify potential GPVI receptor antagonists among FDA-approved drugs. Computational and molecular dynamics simulations revealed that adapalene and ranolazine exhibit strong binding affinities to GPVI receptors and stabilize GPVI proteins, respectively. Both compounds inhibited collagen-induced platelet aggregation, evidenced by the suppression of Syk tyrosine kinase expression, a marker of platelet activation, via GPVI stimulation, as confirmed through flow cytometry analysis. Further analysis using circular dichroism and Raman spectroscopy indicated that collagen exposure induced conformational changes in the α-helical domains of platelets, which were stabilized upon treatment with adapalene and ranolazine. Moreover, thrombotic events can lead to cerebral cell death due to hypoxia, which may be mitigated by neuroprotective compounds. Adapalene and ranolazine were assessed for their neuroprotective capabilities. The results showed that these compounds exhibited neuroprotective effects in SHSY5Y neuroblastoma cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R) injury, reducing HIF-1α expression, ROS production, lipid peroxidation, and caspase-3 levels, while also improving mitochondrial membrane potential and glutathione levels. Acridine orange and propidium iodide staining studies further confirmed a decrease in apoptosis. In the FeCl3-induced carotid artery thrombosis model, ranolazine effectively inhibited platelet aggregation by modulating GPVI receptor activity, reducing intracellular calcium levels, and enhancing cAMP signaling. It also suppressed critical platelet activation mediators, including COX-1, TXB2, and PGE2, thereby mitigating thrombus formation. Collectively, these results suggest that adapalene and ranolazine may serve as multimodal therapeutic agents with the potential to treat both thrombotic and neurological diseases. Future studies focusing on the adapalene and ranolazine molecular mechanisms, bleeding risk, dose titration, and long-term safety while managing thrombotic disorders have to be investigated.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-025-04530-z.

血小板糖蛋白VI受体拮抗剂及其神经保护活性的发现:计算机、体外和体内研究。
本研究利用药物再利用方法在fda批准的药物中鉴定潜在的GPVI受体拮抗剂。计算和分子动力学模拟表明,阿达帕烯和雷诺嗪分别对GPVI受体具有很强的结合亲和力,并能稳定GPVI蛋白。这两种化合物都抑制胶原诱导的血小板聚集,通过GPVI刺激抑制Syk酪氨酸激酶表达证明,Syk酪氨酸激酶是血小板活化的标志,通过流式细胞术分析证实。进一步的圆二色性和拉曼光谱分析表明,胶原暴露引起血小板α-螺旋结构域的构象变化,并在阿达帕烯和雷诺嗪处理后稳定下来。此外,血栓形成事件可导致缺氧导致的脑细胞死亡,这可能由神经保护化合物减轻。评估阿达帕林和雷诺嗪的神经保护能力。结果表明,这些化合物对氧糖剥夺/再灌注(OGD/R)损伤的SHSY5Y神经母细胞瘤细胞具有神经保护作用,可降低HIF-1α表达、ROS生成、脂质过氧化和caspase-3水平,同时提高线粒体膜电位和谷胱甘肽水平。吖啶橙和碘化丙啶染色进一步证实细胞凋亡减少。在fecl3诱导的颈动脉血栓模型中,雷诺嗪通过调节GPVI受体活性、降低细胞内钙水平、增强cAMP信号传导,有效抑制血小板聚集。它还抑制关键的血小板活化介质,包括COX-1、TXB2和PGE2,从而减轻血栓形成。总的来说,这些结果表明阿达帕林和雷诺嗪可能作为多模式治疗药物,具有治疗血栓性和神经系统疾病的潜力。未来的研究重点是阿达帕林和雷诺嗪的分子机制、出血风险、剂量滴定和治疗血栓性疾病的长期安全性。补充信息:在线版本包含补充资料,提供地址为10.1007/s13205-025-04530-z。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
3 Biotech
3 Biotech Agricultural and Biological Sciences-Agricultural and Biological Sciences (miscellaneous)
CiteScore
6.00
自引率
0.00%
发文量
314
期刊介绍: 3 Biotech publishes the results of the latest research related to the study and application of biotechnology to: - Medicine and Biomedical Sciences - Agriculture - The Environment The focus on these three technology sectors recognizes that complete Biotechnology applications often require a combination of techniques. 3 Biotech not only presents the latest developments in biotechnology but also addresses the problems and benefits of integrating a variety of techniques for a particular application. 3 Biotech will appeal to scientists and engineers in both academia and industry focused on the safe and efficient application of Biotechnology to Medicine, Agriculture and the Environment.
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