曹健,張謹(jǐn),呂書(shū)軒,常晉瑞
(1.西安醫(yī)學(xué)院基礎(chǔ)醫(yī)學(xué)部生理教研室,陜西西安710021;2.西安交通大學(xué)醫(yī)學(xué)部生理學(xué)與病理生理學(xué)系,陜西西安710061)
中縫背核內(nèi)5-HT1受體在帕金森病中的調(diào)節(jié)作用
曹健1,張謹(jǐn)2,呂書(shū)軒2,常晉瑞1
(1.西安醫(yī)學(xué)院基礎(chǔ)醫(yī)學(xué)部生理教研室,陜西西安710021;2.西安交通大學(xué)醫(yī)學(xué)部生理學(xué)與病理生理學(xué)系,陜西西安710061)
帕金森病主要病理改變是黑質(zhì)致密部的DA能神經(jīng)元變性壞死,同時(shí)伴隨有DRN中5-HT神經(jīng)元缺失以及5-HT釋放量減少。主要是通過(guò)相關(guān)的5-HT1受體對(duì)5-HT能神經(jīng)元的活動(dòng)起負(fù)反饋抑制作用。也可以通過(guò)與5-HT能神經(jīng)元有突觸聯(lián)系的抑制性的中間神經(jīng)元,間接促進(jìn)其功能活動(dòng)。
5-HT1受體;中縫背核;帕金森病
帕金森病(Parkinson's disease,PD)是一種以運(yùn)動(dòng)系統(tǒng)損害為主的神經(jīng)變性疾病,其主要病理學(xué)改變是黑質(zhì)致密部(substantia nigra pars compacta,SNc)的多巴胺(dopamine,DA)能神經(jīng)元變性壞死導(dǎo)致紋狀體DA含量顯著降低,從而引起的基底神經(jīng)節(jié)的功能紊亂[1-2]。PD的主要病理改變是黑質(zhì)致密部多巴胺(dopamine,DA)能神經(jīng)元的變性壞死,導(dǎo)致紋狀體的DA含量顯著減少,進(jìn)而導(dǎo)致基底神經(jīng)節(jié)環(huán)路的功能紊亂,從而引起PD的運(yùn)動(dòng)系統(tǒng)癥狀。其另一重要病理變化是神經(jīng)元胞質(zhì)中出現(xiàn)一種嗜酸性包涵體路易小體。路易小體不僅出現(xiàn)在SNc,還可見(jiàn)于其他腦區(qū),包括皮層、下丘腦、杏仁核、藍(lán)斑、嗅球、迷走神經(jīng)核、外周自主神經(jīng)系統(tǒng)等[3]。研究表明,這些區(qū)域路易小體的出現(xiàn)可能與PD的非運(yùn)動(dòng)癥狀相關(guān)[2]。
在腦內(nèi),5-羥色胺(5-hydroxytryptamine,5-HT)能神經(jīng)元主要集中在腦干的中縫核團(tuán),其中中縫背核(dorsal raphe nucleus,DRN)是腦內(nèi)5-HT能神經(jīng)元的主要聚集地之一,含有大量的密集的5-HT能神經(jīng)元以及5-HT受體。DRN接受的傳入投射復(fù)雜多樣,它們共同調(diào)節(jié)DRN內(nèi)5-HT能神經(jīng)元的電活動(dòng)及5-HT的釋放。支配調(diào)節(jié)DRN中5-HT神經(jīng)元的纖維的主要區(qū)域包括有內(nèi)側(cè)前額葉皮質(zhì)(the medial prefrontal cortex,mPFC)、外側(cè)韁核(the lateral habenula,LHB)、藍(lán)斑核(locus coreuleus,LC)、一些中腦的區(qū)域比如中腦黑質(zhì)(the substantia nigra,SN)以及中腦導(dǎo)水管周?chē)屹|(zhì)(the periaqueductal gray matter,PAG)和一些下丘腦(hypothalamic,HTL)部分。主要的神經(jīng)遞質(zhì)包括來(lái)自LC的去甲腎上腺素(noradrenaline,NA)、來(lái)自mPFC的谷氨酸(glutamate,Glu)、來(lái)自從HTL和PAG投射而來(lái)的γ-氨基丁酸(γ-aminobutyric acid,GABA)能神經(jīng)遞質(zhì)。從SN和腹側(cè)被蓋區(qū)(ventral tegmental area,VTA)還有纖維投射支配DRN中的DA能神經(jīng)元[4]。
在神經(jīng)系統(tǒng)內(nèi),5-HT是廣泛存在于中樞神經(jīng)系統(tǒng)中的一種單胺類(lèi)神經(jīng)遞質(zhì),主要通過(guò)與5-HT受體結(jié)合發(fā)揮生物學(xué)效應(yīng)。5-HT受體在腦內(nèi)分布廣泛,參與調(diào)節(jié)機(jī)體的多項(xiàng)生理機(jī)能。根據(jù)其分子結(jié)構(gòu)及藥理學(xué)特性,可分為七個(gè)家族(5-HT1~5-HT7),包括至少14種不同的受體亞型[5-6]。除5-HT3受體為配體門(mén)控離子通道型受體外,其余都是七次跨膜的G蛋白耦聯(lián)受體。其中5-HT1受體分為5-HT1A、5-HT1B、5-HT1D、5-HT1E和5-HT1F五種亞型,與細(xì)胞膜上的Gi/o蛋白結(jié)合,激活后抑制環(huán)磷酸腺苷(cyclic adenosine 3',5'-monophosphate,cAMP)的生成。大量證據(jù)表明5-HT1A、5-HT1B、5-HT1D受體對(duì)于DRN中5HT的釋放起重要的調(diào)節(jié)作用,而5-HT1E和5-HT1F受體作用尚不明確[7]。
2.15 -HT1A受體5-HT1A受體在腦內(nèi)分布最為廣泛,在DRN內(nèi)5-HT能神經(jīng)元和GABA能神經(jīng)元都有高密度5-HT1A受體,其更多表達(dá)于5-HT能神經(jīng)元的胞體和樹(shù)突上,作為自身受體調(diào)節(jié)5-HT能神經(jīng)元的活動(dòng)及5-HT的合成和釋放。5-HT1A受體可通過(guò)G蛋白與K+通道相連,激活5-HT1A受體可使K+通道活動(dòng)增強(qiáng)而使細(xì)胞產(chǎn)生超極化,從而抑制5-HT能神經(jīng)元的電活動(dòng),并減少5-HT纖維末梢在胞體周?chē)巴渡鋮^(qū)域的釋放[8]。研究發(fā)現(xiàn)該受體激活后可以緩解焦慮和抑郁的癥狀。此外還與認(rèn)知功能、體溫、攝食和性行為的調(diào)節(jié)有關(guān)[9-10]。
2.25 -HT1B受體5-HT1B受體在腦內(nèi)主要表達(dá)于蒼白球和黑質(zhì)致密,在DRN中也有大量表達(dá),該受體激活后可抑制突觸后電位產(chǎn)生,引起5-HT和乙酰膽堿等遞質(zhì)的釋放減少,參與調(diào)節(jié)情緒、認(rèn)知功能、體溫、疼痛和攝食等功能。在DRN中5-HT1B受體可作為自身受體存在于5-HT能神經(jīng)元的軸突末梢,也可以以異身受體表達(dá)于非5-HT能神經(jīng)元的突觸前膜上[11]??煞謩e通過(guò)5-HT能神經(jīng)元表面的自身受體或者非5-HT能神經(jīng)元的異體受體兩種途徑,調(diào)節(jié)5-HT以及其他包括乙酰膽堿、去甲腎上腺素、DA、GABA、Glu等神經(jīng)遞質(zhì)的釋放?,F(xiàn)有證據(jù)表明5-HT1B受體的活動(dòng)主要更主要是通過(guò)與5-HT有突觸聯(lián)系的抑制性的中間神經(jīng)元,間接促進(jìn)其功能活動(dòng)[11-12]。
2.35 -HT1D受體大鼠體內(nèi)的5-HT1D受體主要分布于SN、蒼白球、尾狀核、殼核、海馬和皮層,在DRN內(nèi)也有適度表達(dá),受體激活后通過(guò)抑制cAMP而減小突觸后電位的產(chǎn)生。該受體與5-HT1B受體在功能上有著相似的效應(yīng),同時(shí)對(duì)5-HT1B受體起協(xié)同作用。激活5-HT1D受體后可使腦內(nèi)5-HT、GABA、Glu釋放減少。選擇性5-HT1D受體激動(dòng)劑舒馬曲坦能有效的抑制DRN中5-HT遞質(zhì)的釋放。
DRN內(nèi)神經(jīng)元的活動(dòng)由核團(tuán)內(nèi)5-HT遞質(zhì)的釋放來(lái)調(diào)節(jié)[13],而5-HT受體可作為自身受體存在于5-HT能神經(jīng)元對(duì)5-HT能神經(jīng)元的活動(dòng)起負(fù)反饋抑制作用。其中5-HT1A受體主要位于神經(jīng)元的胞體,而5-HT1B受體則位于神經(jīng)元的軸突末梢,5-HT1D受體也主要位于軸突末梢也包括部分樹(shù)突。同時(shí)也可以通過(guò)存在于非5-HT能的中間神經(jīng)元上的異身受體進(jìn)而對(duì)5-HT遞質(zhì)的釋放產(chǎn)生調(diào)控。通過(guò)研究發(fā)現(xiàn),三種受體在5-HT與非5-HT能神經(jīng)元都有所表達(dá),但5-HT1A受體以自身受體為主,而5-HT1B與5-HT1D受體更主要通過(guò)異身受體發(fā)揮調(diào)節(jié)作用。
PD主要的病理學(xué)變化是SNc內(nèi)的DA能神經(jīng)元的變性缺失,此外包括NA、乙酰膽堿和5-HT等遞質(zhì)系統(tǒng)也都受到影響[14-15]。PD狀態(tài)下,中縫核群的5-HT能神經(jīng)元丟失,且5-HT能神經(jīng)元內(nèi)出現(xiàn)路易小體,最終引起5-HT遞質(zhì)水平的下降[16-17]。尤其是來(lái)自mPFC的谷氨酸能神經(jīng)纖維的投射,對(duì)DRN 5-HT能神經(jīng)元的活動(dòng)及5-HT遞質(zhì)的釋放發(fā)揮重要的調(diào)節(jié)作用[18]。在6-OHDA單側(cè)損毀SNc的PD大鼠,其VTA的DA能神經(jīng)元可減少,D1、D2受體的下調(diào)減弱了DA能傳入對(duì)mPFC錐體神經(jīng)元的抑制作用,使mPFC的錐體神經(jīng)元過(guò)度興奮。mPFC傳入活動(dòng)增強(qiáng),使DRN中5-HT能神經(jīng)元的興奮,增加了DRN中5-HT遞質(zhì)的釋放。5-HT遞質(zhì)釋放的增多可通過(guò)與5-HT1A自身受體結(jié)合從而抑制了5-HT能神經(jīng)元自身或其他5-HT能神經(jīng)元的活動(dòng),同時(shí)5-HT遞質(zhì)還可與5-HT能神經(jīng)元樹(shù)突及軸突上的5-HT1B和5-HT1D受體結(jié)合抑制突觸后電位產(chǎn)生,引起5-HT等遞質(zhì)的釋放減少。另一方面mPFC興奮了以GABA能為主的中間神經(jīng)元,通過(guò)與中間神經(jīng)元存在的5-HT1B、5-HT1D以及GABAA等受體結(jié)合,對(duì)周?chē)?-HT能神經(jīng)元產(chǎn)生抑制作用。此外,5-HT轉(zhuǎn)運(yùn)體可將細(xì)胞間隙的5-HT重?cái)z取,從而降低胞外5-HT濃度,在5-HT神經(jīng)遞質(zhì)的微調(diào)中起重要作用。而在PD早期,患者中縫核團(tuán)等多個(gè)腦區(qū)中5-羥色胺轉(zhuǎn)運(yùn)體水平顯著降低[19],5-HT的再攝取活動(dòng)受到抑制,從而降低了5-HT遞質(zhì)的釋放(見(jiàn)圖1)。
圖1mPFC錐體神經(jīng)元與DRN 5-HT能神經(jīng)元投射示意圖注:Pyr,Pyramidal neurons錐體神經(jīng)元。
當(dāng)然,PD狀態(tài)下,DRN中還出現(xiàn)其他受體的活動(dòng)變化包括5-HT2、5-HT7和GABAA受體等,均對(duì)5-HT遞質(zhì)活動(dòng)產(chǎn)生重要的調(diào)節(jié)作用,但5-HT1受體特別是5-HT1A表達(dá)量最高,在其中起著關(guān)鍵性的調(diào)節(jié)作用。
PD狀態(tài)下,DRN內(nèi)出現(xiàn)5-HT神經(jīng)元缺失的同時(shí)遞質(zhì)釋放量減少,相關(guān)受體功能活動(dòng)產(chǎn)生變化,其中5-HT1A、5-HT1B、5-HT1D受體發(fā)揮著重要的調(diào)節(jié)作用,與PD的發(fā)生及相關(guān)癥狀的產(chǎn)生密切聯(lián)系,對(duì)5-HT1受體的關(guān)注和研究有望對(duì)PD的預(yù)防與治療提供新的思路。
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Role of dorsal raphe nucleus 5-HT1 receptor in regulating Parkinson's disease.
CAO Jian1,ZHANG Jin2,LV Shu-xuan2,CHANG Jin-rui1.
1.Department of Physiology,School of Basic Medical Science,Xi'an Medical University, Xi'an 710021,Shaanxi,CHINA;2.Department of Physiology and Pathophysiology,Xi’an Jiaotong University Health Science Center,Xi'an 710061,Shaanxi,CHINA
The main pathological change in Parkinson's disease involves the degenerative necrosis of DA neurons in substantia nigra pars compacta,accompanied by the loss of 5-HT neurons in the DRN and a decrease in 5-HT release.It mainly results from the inhibitory feedback control of 5-HT neurons through relevant 5-HT1 receptors,or the indirect functional promotion via a proposed synaptic connection 5-HT-mediated inhibitory interneuronal neurons.
5-HT1 receptor;Dorsal raphe nucleus;Parkinson's disease
R742.5
A
1003—6350(2017)11—1816—03
2017-03-17)
10.3969/j.issn.1003-6350.2017.11.032
陜西省教育廳專(zhuān)項(xiàng)科研計(jì)劃項(xiàng)目(編號(hào):15JK1616);西安醫(yī)學(xué)院配套基金項(xiàng)目(編號(hào):2016PT05);西安醫(yī)學(xué)院博士科研啟動(dòng)基金項(xiàng)目(編號(hào):2015DOC01);西安醫(yī)學(xué)院學(xué)科建設(shè)經(jīng)費(fèi)
曹健。E-mail:littlegrass123@163.com