基于脑-肠轴的芎附汤治疗偏头痛配伍增效机理研究

Xiongfu decoction is composed of Chuanxiong rhizoma and Cyperi rhizoma, which comes from a master of medicine called Danxi Xinfa A vast number of clinical researches have demonstrated that Xiongfu decoction has a definite effect on migraine. Our researches also confirmed that Xiongfu decoction was better than Chuanxiong rhizoma decoction or Cyperi rhizoma decoction in the treatment of migraine; however the synergistic anti-migraine mechanism is still not clear. Chuanxiong rhizoma should be used to treat migraine; however there are no evidences that Cyperi rhizoma can cure migraine. Cyperi rhizoma can regulate the brain-gut peptides about gastrointestinal motility to promote the intestinal absorption. Some brain-gut peptides, including 5-HT, CGRP, VIP, SP and CCK, are both associated with gastrointestinal motility and migraine. Brain-gut peptides in the gastrointestinal tract can interact with brain-gut peptides in the brain via the vagus nerve in the brain-gut axis. Accordingly, a scientific hypothesis is proposed that Xiongfu decoction can play synergistic effects on treating migraine through the brain-gut axis. The effect of promoting intestinal absorption has been analyzed by associating the content of brain-gut peptides in the gastrointestinal tract with the content of active ingredients in the intestinal absorption fluid. The effect of promoting the permeability of blood-brain barrier has been analyzed by associating the permeability of blood-brain barrier with the content of active ingredients in the cerebrospinal fluid. The effect of treating migraine is regulated by the brain-gut peptides in the gastrointestinal tract interacting with the brain-gut peptides in the brain. The increasing content of active ingredients in the intestinal absorption fluid and cerebrospinal fluid, as well as the brain-gut peptides interaction in the brain-gut axis, which are involved in the synergistic anti-migraine mechanism of Xiongfu decoction. This study will not only provide the theoretical support for Xiongfu decoction in the clinical applications, but also enrich the scientific connotation of traditional Chinese medicine compatibility theory.

芎附汤出自《丹溪心法》，以川芎、香附伍用，临床可有效治疗偏头痛。本课题组前期研究亦证实，芎附汤治疗偏头痛效果优于单川芎汤和单香附汤组，但其配伍增效机理尚不明确。头痛须用川芎，而香附治疗偏头痛尚无报道。香附可调节胃肠动力脑肠肽而促进肠吸收，胃肠动力脑肠肽5-HT、CGRP、VIP、SP和CCK等，与偏头痛发作又相关，它们可经迷走神经在脑-肠轴间互动。基于此，预测“芎附汤可通过调控脑-肠轴而发挥治疗偏头痛的协同增效作用”。通过芎附汤中香附伍用川芎促肠吸收作用，辨识胃肠脑肠肽和入肠有效成分的相关性；促透血脑屏障作用，明确血脑屏障通透性和入脑有效成分的相关性；调控脑-肠轴互动作用，分析调节胃肠脑肠肽在脑-肠轴互动而治疗偏头痛的作用途径。阐明芎附汤中香附伍用川芎可促进有效成分吸收入肠、入脑，调控脑肠肽而治疗偏头痛的配伍增效机理，预期可为芎附汤的临床应用提供理论支撑，且可丰富中药配伍理论的科学内涵。

芎附方出自《丹溪心法》，以川芎、香附1:2配伍使用，可有效治疗偏头痛。实验研究发现芎附方可以显著降低偏头痛大鼠血清IL-1β、IL-6、ET-1含量，显著升高血清IL-10、IL-4含量，显著降低偏头痛大鼠脑组织和肠组织CGRP、MMP-2、MMP-9含量，显著降低偏头痛大鼠脑组织Calca、c-Fos、iNOS和nNOS mRNA表达和脑组织c-Fos、iNOS和nNOS蛋白表达。芎附方治疗偏头痛效果优于单川芎和单香附，但其配伍增效机理尚不明确。研究通过芎附方配伍前后的单向在体肠灌流实验，证实川芎香附配伍可促进其各自主要成分吸收入肠入脑，从而说明芎附方配伍后其有效成分吸收增加，促使其药效增强。同时，研究发现切断迷走神经会明显拮抗芎附方抗偏头痛的作用效果，改变脑肠肽的调控，证实芎附方可能通过迷走神经介导的脑-肠轴通路发挥治疗偏头痛的作用。本研究可为芎附方的临床应用提供理论支撑，且可丰富中药配伍理论的科学内涵。