MCP-1参与偏头痛TGVS激活导致外周致敏的机制研究

Migraine is one of the most of common nervous system diseases, and the pathogenesis is still unclear, but most people think the trigeminovascular system (TGVS) activation induced peripheral sensitization play an important role in migraine. Monocyte chemoattractant protein -1 (MCP-1) is an important factor leading to pain. Our study shows that, the expression of MCP-1 is significantly increased in the trigeminal ganglion (TG) neurons of migraine rats, and it means that MCP-1 may be involved in the pathophysiology of migraine. so far, there is no report about the related with MCP-1 and migraine. In the pre-experiment, we have found that TRPV4, is an pain sensitive factor and CGRP, which is a marker of TGVS activation were expression in the TG tissue of migraine rats. There are located in the TG neurons, and regulated by MCP-1. Another, CGRP is expression when the TRPV4 was up-regulation. Therefore, we speculate that "the increased expression of MCP-1 up-regulated the expression of TRPV4, and the TGVS activation induced peripheral sensitization" is a new mechanism of the migraine. We plan to prepare to intervention the animal model and cell model by Ad-si-MCP-1 and Ad-MCP-1 by IF, WB, RT-PCR and whole-cell patch clamp to prove the hypothesis from pros and cons. The results of this study will not only reveal the molecular mechanism of MCP-1 involved in the occurrence of migraine, but also will provide new ideas and targets for the prevention of migraine.

偏头痛是一类常见的神经系统疾病，发病机制不明确。多数认为与三叉神经血管系统TGVS激活导致外周致敏有关。MCP-1是一种重要的导致疼痛发生的因子。研究显示，偏头痛大鼠TGVS的TG内MCP-1表达显著增高，提示MCP-1可能参与偏头痛的病理生理。但MCP-1与偏头痛发生与发展的关系，迄今尚无报道。预实验中我们发现：偏头痛大鼠TG中的疼痛敏感因子TRPV4与CGRP(TGVS激活的标志物)表达上调并共定位，二者受MCP-1调控，且激活TRPV4可上调CGRP。因此我们推测MCP-1上调使TRPV4表达增加，激活TGVS导致外周致敏是偏头痛的新机制。我们拟制备MCP-1基因的重组腺病毒及RNA干扰序列腺病毒，干预偏头痛动物和细胞模型，应用IF、WB、RT-PCR及膜片钳等技术，从正反两方面验证我们的假说。本研究不仅可能揭示MCP-1参与偏头痛发生分子机制，而且也可能为偏头痛防治提供新靶点。

偏头痛是一类常见的神经系统疾病，发病机制仍不明确。但多数认为与三叉神经血管系统 TGVS激活导致外周致敏有关。单核细胞趋化蛋白-1(MCP-1)是一种重要的导致疼痛发生因子。我们的研究显示，偏头痛大鼠TGVS的TG内MCP-1表达显著增高，提示MCP-1可能参与偏头痛的病理生理。预实验中我们发现：偏头痛大鼠TG中的疼痛敏感因子TRPV4与TGVS激活的标志物CGRP表达上调并共定位，二者受MCP-1调控，且激活TRPV4可上调CGPR。因此，我们推测MCP-1上调使TRPV4表达增加，激活TGVS导致外周致敏是偏头痛的新机制。我们拟制备MCP-1基因的重组腺病毒及RNA干扰序列腺病毒，干预偏头痛动物和细胞模型，应用IF、WB、RT-PCR及膜片钳等技术，从正反两方面验证我们的假说。本研究不仅可能揭示MCP-1参与偏头痛发生分子机制，而且也可能为偏头痛防治提供新靶点。. 本项目研究表明外源性注射MCP-1会易化头痛的发生，抑制MCP-1基因对偏头痛有保护作用，且MCP-1基因通过PLC/PKA/PKC调节外周伤害感受器TRPV4功能，引起三叉神经血管系统(TGVS)的激活导致外周致敏从而参与偏头痛的病理生理机制。研究中发现，MCP-1及其受体CCR2的上调表达与在GTN诱发的偏头痛大鼠模型中，机械痛阈值、畏光以及抓耳挠头等与偏头痛头痛相关的行为学和TG神经元中CGRP的释放、c-FOS高表达均呈正相关。膜片钳实验表明MCP-1能增强TG神经元的兴奋性，其可能的机制是通过激活受体CCR2，引起TG神经元内PLC/PKA/PKC信号途径的激活，从而影响外周伤害感受器TRPV4的功能而实现的。同时研究还发现，MCP-1能够显著改善对TTX-S钠电流的增加幅度，这些实验数据提示MCP-1 介导外周伤害感受器TRPV4，影响TG神经元上离子通道的敏感性改变神经元的兴奋性，导致外周三叉神经血管系统的激活而引发偏头痛的发生与发展，为探索治疗偏头痛新药的新靶点，寻求安全有效的防治药物提供新思路。.