从CGRP介导的信号转导研究芎芷地龙汤中“风药”干预偏头痛的增效机制

Migraine is a syndrome of nervous system and non-nervous system, a series of symptoms of the migraine involving the trigeminovascular system (TVS), calcitonin gene related peptide (CGRP) release in the different anatomical level after TVS activated,and further activate the signaling cascade reaction of CGRP reaction receptor, inducing headache and a series of complex symptoms.At present, CGRP and its receptors are the promising targets for the treatment of migraine.In the treatment of migraine with traditional Chinese medicine,medical practitioners of the past dynasties paid more attention to applying "wind drug",clinical efficacy Significantly improved when applying "wind drug" to treatment migraine.The research group had studied the effects of xiongzhi Dilong Decoction,which can dispel the wind, invigorate the circulation of blood, and dredge collateral on migraine, This prescription attaches importance to the application of "wind drug".To further investigate the synergistic mechanism of "wind drug",Base on the CGRP mediated signal transduction,this project will study the effect of "wind drug(Expelling the external wind drug,Calming internal wind drug)" in Xiongzhi Dilong Decoction on ethology of migraine animal, the function state of meningeal vascular,CGRP related signal transduction in the trigeminovascular system，target metabolites and metabolic pathways.The completion of the study provides important theoretical and scientific basis for clarifying the synergistic mechanism of "wind drug" in treating migraine, and has important scientific significance and academic value in finding the material basis for preventing and treating migraine with traditional Chinese medicine.

偏头痛是一种神经系统和非神经系统表现的综合征，其发病过程中涉及三叉神经血管系统（TVS），TVS激活后，降钙素基因相关肽（CGRP）在不同的解剖水平释放，进一步激活CGRP反应受体信号级联反应，诱发头痛及一系列复杂症状的发生，目前，CGRP及其受体正作为治疗偏头痛有前途的靶标。在中医药防治偏头痛中，“风药”的应用受到历代医家的重视，应用“风药”治疗偏头痛，疗效显著提高。前期课题组研究了祛风活血通络方药芎芷地龙汤对偏头痛的作用，本方配伍强调“风药”的应用，为进一步探讨“风药”的增效机制，本研究从CGRP介导的信号转导方面，研究芎芷地龙汤中“风药（外风药、内风药）”对偏头痛模型行为学、脑膜血管功能状态、三叉神经血管系统CGRP相关信号转导的调节作用，对靶点代谢物及代谢路径的影响。课题的完成对阐明“风药”治疗偏头痛的增效机制提供重要的理论依据，对寻找中医药防治偏头痛的物质基础具有重要的科学意义。

项目背景.近年研究表明，偏头痛发病与三叉神经血管系统功能紊乱密切相关，其中降钙素基因相关肽（CGRP）能够调节神经源性炎症和伤害性信息传入，可能在偏头痛的病理生理中发挥重要作用。偏头痛属“头风”范畴，因此在治疗中多重视“风药”的应用，治以祛风和息风。芎芷地龙汤由外风药川芎、白芷及内风药地龙与延胡索、生石膏等五味药组成，为进一步研究其中风药的增效作用，以三叉神经血管系统CGRP信号转导为切入点，阐释其现代科学内涵。.研究内容.运用分子生物学、代谢组学等技术，研究芎芷地龙汤中风药配伍对CGRP信号转导的影响，及其对代谢物、代谢路径的影响差异。观察连续7天进行硬脑膜注射后的偏头痛动物行为症状、痛阈、硬脑膜血浆渗透率、血浆代谢物、CGRP及下游效应因子等，研究芎芷地龙汤的干预机制及其中风药的增效作用。.重要结果.药物干预10天、硬脑膜注射7天，芎芷地龙汤及芎芷地龙汤去内风药组、芎芷地龙汤去外风药组均可以减少偏头痛模型动物爬笼、左后肢挠头、修面等行为，提高须垫部机械痛阈值及尾部温度痛阈值，降低颈静脉血中血管活性物质水平，降低三叉神经血管系统中相关蛋白表达水平，其中尤以芎芷地龙汤全方组作用最优。.血浆代谢组研究发现芎芷地龙汤全方主要通过调节甘油磷脂代谢，亚油酸代谢，缬氨酸、亮氨酸和异亮氨酸生物合成和酪氨酸代谢发挥改善偏头痛的作用；芎芷地龙汤去内风药组在调节缬氨酸、亮氨酸和异亮氨酸生物合成和酪氨酸代谢方面发挥重要作用，芎芷地龙汤去外风药组在调节酪氨酸代谢方面发挥重要作用。.科学意义.连续7天进行硬脑膜注射CGRP可诱发偏头痛动物模型机械痛阈、温度痛阈降低，诱导三叉神经血管系统CGRP相关的细胞信号转导，导致痛觉信号的传递和放大。.芎芷地龙汤及芎芷地龙汤去外风药组、芎芷地龙汤去内风药组能够调节三叉神经血管系统中CGRP相关的信号传递过程，进而改善偏头痛相关症状，起到预防和治疗偏头痛的作用。其中包含内风药及外风药共同配伍的芎芷地龙汤全方作用最佳。