垂体腺苷酸环化酶激活肽及其受体变化在偏头痛中的作用
发布时间：2018-11-15 13:18
【摘要】：偏头痛是神经内科最常见的疾病之一,其发病机制尚不完全清楚,近年来的研究发现外源性垂体腺苷酸环化酶激活肽(pituitary adenylate cyclase-activating polypeptide,PACAP)能够诱发偏头痛发作,提示PACAP可能参与偏头痛的发病机制,但对于内源性PACAP在整个偏头痛发病过程中外周及中枢的具体变化规律以及何种相关受体在其中起主要作用目前尚不清楚。因此本研究的目的是探讨内源性PACAP及其相关受体变化在偏头痛中的作用。为了探明临床头痛患者外周血PACAP水平的改变及其临床意义,本研究的临床部分首先应用酶联免疫吸附方法比较了133例偏头痛患者、106例紧张型头痛患者以及50例健康对照者的外周血PACAP水平并对其与头痛临床特点进行关联性分析;动物研究部分通过反复电刺激和化学刺激上矢状窦旁硬脑膜建立两种偏头痛大鼠模型,运用放射免疫方法、Western-blot及RT-PCR方法探讨了反复刺激过程中不同刺激天数对外周血及痛觉传导通路(三叉神经节及脑干组织)中内源性PACAP改变的影响,以及PACAP相关的三类受体(PAC1、VPAC1以及VPAC2)在此过程中蛋白及mRNA的表达改变。研究结果发现偏头痛患者发作间期外周血PACAP水平显著低于紧张型头痛患者及健康对照者,进一步分型后发现发作性偏头痛及慢性偏头痛组分别显著低于发作性紧张型头痛与慢性紧张型头痛组,并且发现慢性偏头痛患者的外周血PACAP水平与病程年数呈负相关。动物研究发现在电刺激模型中,外周血及三叉神经节中PACAP明显升高,PAC1和VPAC1受体在三叉神经节、脑干中均有明显的表达上调,VPAC2受体仅在三叉神经节中发现高表达;而在慢性化学刺激模型中,三叉神经节中PACAP水平随着刺激天数的增加明显降低,PAC1受体在三叉神经节中存在表达上调,VPAC1和VPAC2受体无明显改变。综上所述,本研究临床部分首次报道了偏头痛患者外周血PACAP水平显著低于紧张型头痛患者,为临床上这两种最常见且难以鉴别的原发性头痛的鉴别诊断提供了新的思路;而运用两种偏头痛大鼠模型的动物实验发现在反复刺激过程中存在PACAP在急性刺激时的过度释放以及慢性化过程中的PACAP耗竭和相关受体的表达上调,进一步证实了PACAP及其受体在偏头痛发病过程中的重要作用并为寻找偏头痛精准治疗的新靶点提供了理论基础。
[Abstract]:Migraine is one of the most common diseases in neurology, and its pathogenesis is not completely clear. Recent studies have found that exogenous pituitary adenylate cyclase activating peptide (pituitary adenylate cyclase-activating polypeptide,PACAP) can induce migraine attacks. It is suggested that PACAP may be involved in the pathogenesis of migraine, but it is not clear which receptor plays a major role in the specific changes of peripheral and central nervous system during the pathogenesis of migraine by endogenous PACAP. The purpose of this study was to investigate the role of endogenous PACAP and its related receptors in migraine. In order to find out the change of PACAP level in peripheral blood of patients with headache and its clinical significance, the clinical part of this study compared 133 patients with migraine with enzyme linked immunosorbent assay (Elisa). The levels of PACAP in peripheral blood of 106 patients with tension-type headache and 50 healthy controls were analyzed. In animal studies, two kinds of migraine rat models were established by repeated electrical stimulation and chemical stimulation of the superior sagittal sinus dura mater, and radioimmunoassay was used. Western-blot and RT-PCR methods were used to investigate the effects of different stimulation days on the changes of endogenous PACAP in peripheral blood and pain conduction pathway (trigeminal ganglion and brain stem) during repeated stimulation, as well as three types of PACAP related receptors (PAC1,). VPAC1 and VPAC2) change the expression of protein and mRNA during this process. The results showed that the level of PACAP in patients with migraine during interictal period was significantly lower than that in patients with tension-type headache and healthy controls. After further classification, it was found that paroxysmal migraine and chronic migraine were significantly lower than those of paroxysmal tension headache and chronic tension headache, and the level of PACAP in peripheral blood of patients with chronic migraine was negatively correlated with the number of years of disease course. In animal model of electrical stimulation, PACAP in peripheral blood and trigeminal ganglion was significantly increased, PAC1 and VPAC1 receptors were up-regulated in trigeminal ganglion and brain stem, and VPAC2 receptor was only overexpressed in trigeminal ganglion. However, in chronic chemical stimulation model, the level of PACAP in trigeminal ganglion decreased significantly with the increase of stimulation days. The expression of PAC1 receptor was up-regulated in trigeminal ganglion, but VPAC1 and VPAC2 receptors did not change significantly. To sum up, the clinical part of this study reported for the first time that the level of PACAP in peripheral blood of migraine patients was significantly lower than that of tension headache patients, which provided a new idea for the differential diagnosis of these two most common and difficult to differentiate primary headache. The animal experiments of two migraine rat models showed that the excessive release of PACAP during acute stimulation and the depletion of PACAP and the up-regulation of related receptors in the course of chronic stimulation existed during repeated stimulation. The important role of PACAP and its receptors in the pathogenesis of migraine is further confirmed and the theoretical basis for finding new targets for accurate treatment of migraine is provided.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R747.2
[Abstract]:Migraine is one of the most common diseases in neurology, and its pathogenesis is not completely clear. Recent studies have found that exogenous pituitary adenylate cyclase activating peptide (pituitary adenylate cyclase-activating polypeptide,PACAP) can induce migraine attacks. It is suggested that PACAP may be involved in the pathogenesis of migraine, but it is not clear which receptor plays a major role in the specific changes of peripheral and central nervous system during the pathogenesis of migraine by endogenous PACAP. The purpose of this study was to investigate the role of endogenous PACAP and its related receptors in migraine. In order to find out the change of PACAP level in peripheral blood of patients with headache and its clinical significance, the clinical part of this study compared 133 patients with migraine with enzyme linked immunosorbent assay (Elisa). The levels of PACAP in peripheral blood of 106 patients with tension-type headache and 50 healthy controls were analyzed. In animal studies, two kinds of migraine rat models were established by repeated electrical stimulation and chemical stimulation of the superior sagittal sinus dura mater, and radioimmunoassay was used. Western-blot and RT-PCR methods were used to investigate the effects of different stimulation days on the changes of endogenous PACAP in peripheral blood and pain conduction pathway (trigeminal ganglion and brain stem) during repeated stimulation, as well as three types of PACAP related receptors (PAC1,). VPAC1 and VPAC2) change the expression of protein and mRNA during this process. The results showed that the level of PACAP in patients with migraine during interictal period was significantly lower than that in patients with tension-type headache and healthy controls. After further classification, it was found that paroxysmal migraine and chronic migraine were significantly lower than those of paroxysmal tension headache and chronic tension headache, and the level of PACAP in peripheral blood of patients with chronic migraine was negatively correlated with the number of years of disease course. In animal model of electrical stimulation, PACAP in peripheral blood and trigeminal ganglion was significantly increased, PAC1 and VPAC1 receptors were up-regulated in trigeminal ganglion and brain stem, and VPAC2 receptor was only overexpressed in trigeminal ganglion. However, in chronic chemical stimulation model, the level of PACAP in trigeminal ganglion decreased significantly with the increase of stimulation days. The expression of PAC1 receptor was up-regulated in trigeminal ganglion, but VPAC1 and VPAC2 receptors did not change significantly. To sum up, the clinical part of this study reported for the first time that the level of PACAP in peripheral blood of migraine patients was significantly lower than that of tension headache patients, which provided a new idea for the differential diagnosis of these two most common and difficult to differentiate primary headache. The animal experiments of two migraine rat models showed that the excessive release of PACAP during acute stimulation and the depletion of PACAP and the up-regulation of related receptors in the course of chronic stimulation existed during repeated stimulation. The important role of PACAP and its receptors in the pathogenesis of migraine is further confirmed and the theoretical basis for finding new targets for accurate treatment of migraine is provided.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R747.2
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