【摘要】：偏頭痛是神經(jīng)內(nèi)科最常見(jiàn)的疾病之一,其發(fā)病機(jī)制尚不完全清楚,近年來(lái)的研究發(fā)現(xiàn)外源性垂體腺苷酸環(huán)化酶激活肽(pituitary adenylate cyclase-activating polypeptide,PACAP)能夠誘發(fā)偏頭痛發(fā)作,提示PACAP可能參與偏頭痛的發(fā)病機(jī)制,但對(duì)于內(nèi)源性PACAP在整個(gè)偏頭痛發(fā)病過(guò)程中外周及中樞的具體變化規(guī)律以及何種相關(guān)受體在其中起主要作用目前尚不清楚。因此本研究的目的是探討內(nèi)源性PACAP及其相關(guān)受體變化在偏頭痛中的作用。為了探明臨床頭痛患者外周血PACAP水平的改變及其臨床意義,本研究的臨床部分首先應(yīng)用酶聯(lián)免疫吸附方法比較了133例偏頭痛患者、106例緊張型頭痛患者以及50例健康對(duì)照者的外周血PACAP水平并對(duì)其與頭痛臨床特點(diǎn)進(jìn)行關(guān)聯(lián)性分析;動(dòng)物研究部分通過(guò)反復(fù)電刺激和化學(xué)刺激上矢狀竇旁硬腦膜建立兩種偏頭痛大鼠模型,運(yùn)用放射免疫方法、Western-blot及RT-PCR方法探討了反復(fù)刺激過(guò)程中不同刺激天數(shù)對(duì)外周血及痛覺(jué)傳導(dǎo)通路(三叉神經(jīng)節(jié)及腦干組織)中內(nèi)源性PACAP改變的影響,以及PACAP相關(guān)的三類受體(PAC1、VPAC1以及VPAC2)在此過(guò)程中蛋白及mRNA的表達(dá)改變。研究結(jié)果發(fā)現(xiàn)偏頭痛患者發(fā)作間期外周血PACAP水平顯著低于緊張型頭痛患者及健康對(duì)照者,進(jìn)一步分型后發(fā)現(xiàn)發(fā)作性偏頭痛及慢性偏頭痛組分別顯著低于發(fā)作性緊張型頭痛與慢性緊張型頭痛組,并且發(fā)現(xiàn)慢性偏頭痛患者的外周血PACAP水平與病程年數(shù)呈負(fù)相關(guān)。動(dòng)物研究發(fā)現(xiàn)在電刺激模型中,外周血及三叉神經(jīng)節(jié)中PACAP明顯升高,PAC1和VPAC1受體在三叉神經(jīng)節(jié)、腦干中均有明顯的表達(dá)上調(diào),VPAC2受體僅在三叉神經(jīng)節(jié)中發(fā)現(xiàn)高表達(dá);而在慢性化學(xué)刺激模型中,三叉神經(jīng)節(jié)中PACAP水平隨著刺激天數(shù)的增加明顯降低,PAC1受體在三叉神經(jīng)節(jié)中存在表達(dá)上調(diào),VPAC1和VPAC2受體無(wú)明顯改變。綜上所述,本研究臨床部分首次報(bào)道了偏頭痛患者外周血PACAP水平顯著低于緊張型頭痛患者,為臨床上這兩種最常見(jiàn)且難以鑒別的原發(fā)性頭痛的鑒別診斷提供了新的思路;而運(yùn)用兩種偏頭痛大鼠模型的動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)在反復(fù)刺激過(guò)程中存在PACAP在急性刺激時(shí)的過(guò)度釋放以及慢性化過(guò)程中的PACAP耗竭和相關(guān)受體的表達(dá)上調(diào),進(jìn)一步證實(shí)了PACAP及其受體在偏頭痛發(fā)病過(guò)程中的重要作用并為尋找偏頭痛精準(zhǔn)治療的新靶點(diǎn)提供了理論基礎(chǔ)。
[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.
【學(xué)位授予單位】：清華大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R747.2

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 尹麗媛,林莉,談?dòng)哑?于靜濤,劉純義;牙髓炎癥時(shí)膠質(zhì)源性神經(jīng)營(yíng)養(yǎng)因子在三叉神經(jīng)節(jié)內(nèi)的表達(dá)[J];解剖科學(xué)進(jìn)展;2000年04期

2 張奎啟,王福,仲維劍,張?jiān)?三叉神經(jīng)節(jié)的動(dòng)脈供應(yīng)[J];中華口腔醫(yī)學(xué)雜志;2001年01期

3 林莉,于靜濤,劉純義;牙齒損傷時(shí)神經(jīng)生長(zhǎng)因子和降鈣素基因相關(guān)肽在三叉神經(jīng)節(jié)中的表達(dá)變化[J];解剖科學(xué)進(jìn)展;2002年02期

4 李付勇,衣服新,馬逸,郭文師,孫愛(ài)剛;微球囊壓迫三叉神經(jīng)節(jié)對(duì)兔三叉神經(jīng)的抑制作用[J];錦州醫(yī)學(xué)院學(xué)報(bào);2005年05期

5 黃飛;張敏;張e，

本文編號(hào)：2333417