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对多发性硬化症的药物重新定位和查针对微细胞和巨细胞
Nandi Bao1, Jing Liu2, Heran Wang2
1Senior Department of Cardiology, the Sixth Medical Center of PLA General Hospital, Beijing, 100048, China.
微/巨细胞 (MG/Mφ) 是多发性硬化症 (MS) 病原体的关键. 新的候选药物,eliprodil和volinanserin,通过向NMDA受体来减少炎症和细胞毒性.
科学领域:
- 神经免疫学 神经免疫学
- 药理学 药理学是指药理学的学科.
背景情况:
- 微/巨细胞 (MG/Mφ) 是多发性硬化症 (MS) 病原体的核心.
- 目前的多发性硬化治疗有局限性,需要针对MG/Mφ的新型治疗策略.
- 在MS中MG/Mφ亚群的异质性和调节机制仍然不完全理解.
研究的目的:
- 为了研究MS病变的MG/Mφ亚群.
- 识别和评估针对MS治疗的针对MG/Mφ的新型治疗剂.
- 阐明潜在候选药物的作用机制.
主要方法:
- 在实验性自身免疫脑膜炎 (EAE) 期间识别和描述MG/Mφ亚群.
- 在分析中,包括对N-甲基-D-酸盐 (NMDA) 受体进行化合物的虚拟对接.
- 在体外验证候选化合物的抗炎和细胞毒性作用.
- 使用CoMFA和拓体CoMFA进行定量结构-活动关系 (QSAR) 建模.
主要成果:
- 确定了三个不同的MG/Mφ亚群,MG/Mφ_3在EAE进展过程中增加.
- 伊芬产和RO-25-6981抑制了炎症因素并降低了细胞毒性.
- 虚拟对接确定了eliprodil和volinanserin作为潜在的低结合能量的化合物,向NMDA受体.
- 在体外研究证实了eliprodil和volinanserin在减少炎症的有效性,其细胞毒性最小.
- 开发了CoMFA和拓体CoMFA模型,为改善药物设计提供了结构性见解.
结论:
- MG/Mφ在MS相关的炎症途径中起着重要作用.
- 埃利普罗迪尔和伏利南塞林通过通过NMDA受体相互作用调节MG/Mφ活性,显示出作为MS治疗药物的潜力.
- 这项研究为开发针对MS的向治疗提供了基础,重点关注MG/Mφ和NMDA受体通路.
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