王 弘 喬德才 劉曉莉

(北京師范大學(xué)體育與運(yùn)動(dòng)學(xué)院，北京 100875)

A2AR/D2DR在運(yùn)動(dòng)調(diào)節(jié)帕金森病基底神經(jīng)節(jié)功能紊亂中的作用研究進(jìn)展

王 弘 喬德才 劉曉莉

(北京師范大學(xué)體育與運(yùn)動(dòng)學(xué)院，北京 100875)

腺苷A2A型受體；多巴胺D2型受體；帕金森??；紋狀體；運(yùn)動(dòng)調(diào)控

帕金森病(PD)是一種神經(jīng)系統(tǒng)退行性疾病，主要病理性改變?yōu)楹谫|(zhì)致密部多巴胺(DA)能神經(jīng)元變性、壞死，紋狀體DA投射減少，引發(fā)黑質(zhì)-紋狀體通路對(duì)基底神經(jīng)節(jié)的調(diào)節(jié)功能紊亂〔1〕。DA替代治療在PD早期能夠緩解其臨床癥狀〔2〕，但隨著病情發(fā)展，患者會(huì)對(duì)以左旋多巴(L-DOPA)為主的DA能抗PD藥物產(chǎn)生耐藥性、引發(fā)異動(dòng)癥等并發(fā)癥〔3〕。近年來研究證實(shí)，腺苷A2A型受體(A2AR)拮抗劑具有增強(qiáng)多巴胺D2型受體(D2DR)活性的作用〔4〕，能有效緩解PD的臨床癥狀〔5〕，且副作用較小〔6〕，迅速成為PD治療的新策略。堅(jiān)持規(guī)律運(yùn)動(dòng)可以減緩由于增齡引發(fā)A2AR活性增高的過程〔7，8〕，這可能與近年來文獻(xiàn)報(bào)道的運(yùn)動(dòng)療法顯著改善PD 病人行為功能障礙有關(guān)，提示A2AR/D2DR在運(yùn)動(dòng)調(diào)節(jié)PD狀態(tài)下基底神經(jīng)節(jié)功能紊亂中起重要作用。

1 A2AR/D2DR與基底神經(jīng)節(jié)運(yùn)動(dòng)調(diào)節(jié)環(huán)路

基底神經(jīng)節(jié)是參與運(yùn)動(dòng)行為調(diào)控的皮層下中樞，它主要通過直接通路(direct pathway)與間接通路(indirect pathway)實(shí)現(xiàn)對(duì)運(yùn)動(dòng)功能的調(diào)節(jié)。直接通路是從包括尾狀核和殼核在內(nèi)的新紋狀體(Str)向黑質(zhì)網(wǎng)狀部(SNr)和蒼白球內(nèi)側(cè)部(GPi)發(fā)出單突觸的γ-氨基丁酸(GABA)能神經(jīng)投射，該通路激活會(huì)導(dǎo)致輸出核團(tuán)中神經(jīng)元的抑制，從而使丘腦的抑制解除，并增強(qiáng)對(duì)運(yùn)動(dòng)皮層的興奮性驅(qū)動(dòng)。相反，GABA能紋狀體-蒼白球神經(jīng)元是從紋狀體到黑質(zhì)網(wǎng)狀部這一間接通路的起始端，它的興奮會(huì)增強(qiáng)丘腦底核(STN)向黑質(zhì)網(wǎng)狀部投射的谷氨酸(Glu)能神經(jīng)傳遞，繼而增加對(duì)丘腦的抑制性輸入，導(dǎo)致皮層的興奮性驅(qū)動(dòng)減少〔9〕。因此，間接通路的過度激活或直接通路與間接通路的平衡失調(diào)均可導(dǎo)致運(yùn)動(dòng)功能障礙。

紋狀體是基底神經(jīng)節(jié)直接與間接兩條通路的起始部位，其神經(jīng)元構(gòu)筑約95%為GABA能中等多棘神經(jīng)元(MSNs)，其余為大膽堿能無棘中間神經(jīng)元和快放電中間神經(jīng)元。MSNs分為兩類：即表達(dá)D1DR的GABA能強(qiáng)啡肽神經(jīng)元和表達(dá)D2DR 的GABA能腦啡肽神經(jīng)元〔10〕。紋狀體MSNs樹突棘的“頭”接收來自大腦皮層Glu能的興奮性投射，而樹突棘的“頸部”接受來自黑質(zhì)致密部的DA能投射〔11〕。黑質(zhì)-紋狀體通路的DA信號(hào)可通過上述解剖結(jié)構(gòu)調(diào)節(jié)Glu能突觸傳遞、激活直接通路(D1-MSNs介導(dǎo))和抑制間接通路(D2-MSNs介導(dǎo))發(fā)揮對(duì)運(yùn)動(dòng)的調(diào)控功能。

腺苷是一種內(nèi)源性嘌呤核苷酸，分布于哺乳動(dòng)物的多種組織中,它作為一種神經(jīng)調(diào)質(zhì)參與多種神經(jīng)遞質(zhì)的釋放或突觸后神經(jīng)元電活動(dòng)的調(diào)節(jié)，被認(rèn)為是調(diào)節(jié)神經(jīng)系統(tǒng)穩(wěn)態(tài)的重要物質(zhì)。腺苷有4種受體亞型，分別是A1、A2A、A2B和A3，存在于中樞神經(jīng)系統(tǒng)以及心臟、腎臟、睪丸等不同組織，A2AR在基底神經(jīng)節(jié)紋狀體、蒼白球外側(cè)部分布密度較高〔12〕。逆轉(zhuǎn)錄多聚酶鏈反應(yīng)技術(shù)檢測結(jié)果表明，A2AR mRNA在皮層、杏仁核、海馬、丘腦、小腦等部位也有低水平表達(dá)〔13〕。單克隆抗體超微結(jié)構(gòu)分析結(jié)果顯示，A2AR多分布于突觸后膜，少量分布于突觸前膜；位于突觸前的A2AR起負(fù)反饋調(diào)節(jié)作用，抑制Ca2+內(nèi)流及神經(jīng)遞質(zhì)的釋放，而位于突觸后的A2AR通過與其他受體形成二聚體發(fā)揮生物作用〔14〕。紋狀體D2-MSNs的胞膜上〔15〕、皮層-紋狀體Glu能神經(jīng)元的軸突末梢和紋狀體-蒼白球外側(cè)部GABA能神經(jīng)元的軸突末梢都分布有A2AR-D2DR異源二聚體，見圖1。

A：生理狀態(tài)，B:PD狀態(tài)；實(shí)線的加粗表示興奮性或抑制性變強(qiáng)，虛線表示變?nèi)鯃D1 PD基底神經(jīng)節(jié)A2AR/D2DR共定位及運(yùn)動(dòng)環(huán)路活性變化模式圖

A2AR/D2DR都屬于胞膜上的一種G蛋白耦聯(lián)受體(GPCR)，通過變構(gòu)與配體結(jié)合或與其他受體相互作用形成多聚體聚合物，后者又被稱為受體群島或受體馬賽克，具有不同的生物化學(xué)效能〔16～19〕。本實(shí)驗(yàn)室前期研究表明，A2AR/D2DR共表達(dá)于紋狀體D2-MSNs 的胞膜上，運(yùn)動(dòng)過程中A2AR與D2DR通過獨(dú)立或相互作用影響各自配體與受體結(jié)合，對(duì)腺苷酸環(huán)化酶(AC)產(chǎn)生互為拮抗的作用，生成環(huán)磷酸腺苷(cAMP)，調(diào)節(jié)蛋白激酶(PK)A活性，最終影響紋狀體內(nèi)細(xì)胞信號(hào)整合因子 DARPP-32 的磷酸化〔20〕，這一DA和cAMP調(diào)節(jié)的磷蛋白可被鈣調(diào)磷酸酶(PP-2B)去磷酸化，起到抑制胞外Ca2+內(nèi)流的作用〔21〕。激活A(yù)2AR可興奮紋狀體-蒼白球通路的GABA能神經(jīng)元、激活間接通路，從而起到抑制運(yùn)動(dòng)的作用。相反，激動(dòng)D2DR可抑制紋狀體-蒼白球通路的GABA能神經(jīng)元、抑制間接通路，從而起到易化運(yùn)動(dòng)的作用，見圖2。

+：興奮作用，-：抑制作用圖2 紋狀體A2AR/D2DR胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)機(jī)制模式圖

2 A2AR/D2DR與PD

研究表明，PD狀態(tài)下紋狀體A2AR mRNA表達(dá)顯著升高〔22，23〕、D2DR密度顯著降低〔24〕。核磁共振成像(MRI)結(jié)果表明，PD患者接受A2AR拮抗劑SYN115治療后，丘腦血流量顯著下降，說明蒼白球外側(cè)部對(duì)丘腦的過度抑制得到明顯緩解〔25〕。研究還發(fā)現(xiàn)，PD患者采用A2AR拮抗劑治療后，能夠有效緩解L-DOPA藥物毒作用引發(fā)的異動(dòng)癥等并發(fā)癥〔26，27〕，表明L-DOPA和A2AR拮抗劑的協(xié)同作用對(duì)PD治療有重要的臨床意義〔28〕。此外，新近的研究證實(shí)，拮抗A2AR對(duì)DA能神經(jīng)元具有保護(hù)作用。Fox等人發(fā)現(xiàn)，A2AR拮抗劑可抑制單胺氧化酶的活性，減輕神經(jīng)毒素MPTP對(duì)黑質(zhì)DA能神經(jīng)元的損傷〔29，30〕。有研究發(fā)現(xiàn)，A2AR參與DA合成代謝的調(diào)節(jié)，咖啡因和A2AR拮抗劑MSX-3均可促進(jìn)PD模型動(dòng)物紋狀體DA合成限速酶酪氨酸羥化酶(TH)的合成〔31，32〕。

PD狀態(tài)下紋狀體DA的損耗和丟失對(duì)皮層-紋狀體Glu能突觸傳遞產(chǎn)生去抑制作用〔33，34〕，增強(qiáng)了該通路Glu能突觸傳遞效能，因此Glu的興奮性毒作用也是導(dǎo)致PD狀態(tài)下出現(xiàn)行為功能障礙和異動(dòng)癥等并發(fā)癥的原因之一〔35〕。A2AR和mGluR5在皮層-紋狀體Glu能突觸末梢共定位，A2AR對(duì)紋狀體Glu能神經(jīng)輸入也具有調(diào)節(jié)作用〔36〕，阻斷A2AR能減少皮層Glu的釋放和紋狀體Glu的內(nèi)流〔29〕。Peterson等〔37〕的研究表明，A2AR拮抗劑SCH-58261可以顯著改善DA缺失小鼠D2-MSNs的興奮性、抑制突觸后電流、減輕Glu的興奮性毒性作用。近來有人利用光遺傳技術(shù)進(jìn)一步證實(shí)，用光刺激注射了熒光蛋白標(biāo)記的腺病毒ChR2的野生型小鼠紋狀體 D2-MSNs時(shí)，出現(xiàn)了震顫等PD癥狀且行走和精細(xì)動(dòng)作顯著減少，而雙側(cè)光照紋狀體D1-MSNs則震顫現(xiàn)象得到緩解，與靜止相比，行走等運(yùn)動(dòng)的時(shí)長所占總時(shí)長的百分比明顯增加，初步證實(shí)了PD病理狀態(tài)下間接通路興奮性升高、直接通路興奮性降低可能是導(dǎo)致行為功能障礙的原因，并提出激活直接通路可以作為今后PD的一種治療方案〔38〕。

3 A2AR/D2DR在運(yùn)動(dòng)改善PD基底神經(jīng)節(jié)功能紊亂中的作用

流行病學(xué)調(diào)查發(fā)現(xiàn)，體力活動(dòng)能夠提高PD患者的日常生活能力，降低PD的發(fā)生率和致死率〔8〕。PD患者通過太極拳〔39〕、探戈和拳擊〔40〕等運(yùn)動(dòng)可明顯改善行為功能障礙。大量的研究證實(shí)，運(yùn)動(dòng)防治PD的神經(jīng)生物學(xué)機(jī)制與運(yùn)動(dòng)的神經(jīng)保護(hù)作用有關(guān)〔41〕。Gerecke等〔42〕的研究表明，跑輪運(yùn)動(dòng)可降低PD模型大鼠黑質(zhì)DA能神經(jīng)元的死亡率；Yoon等〔43〕對(duì)6-OHDA模型大鼠連續(xù)進(jìn)行30min/d、14d的跑臺(tái)運(yùn)動(dòng)訓(xùn)練后發(fā)現(xiàn)，黑質(zhì)-紋狀體DA神經(jīng)元的損傷程度明顯降低；Tillerson等〔44〕的研究發(fā)現(xiàn)，6-OHDA模型大鼠進(jìn)行運(yùn)動(dòng)干預(yù)后，黑質(zhì)和紋狀體區(qū)域的TH陽性表達(dá)均明顯提高；Fisher等〔45〕的研究發(fā)現(xiàn)，MPTP小鼠接受運(yùn)動(dòng)訓(xùn)練后，紋狀體多巴胺轉(zhuǎn)運(yùn)體(DAT)表達(dá)下降，而D2DR表達(dá)增加；采用同位素標(biāo)記的受體顯像技術(shù)觀察發(fā)現(xiàn)，運(yùn)動(dòng)增加PD小鼠紋狀體D2DR結(jié)合潛能〔46〕。本實(shí)驗(yàn)室前期研究也表明，4周跑臺(tái)運(yùn)動(dòng)可上調(diào)6-OHDA大鼠紋狀體D2DR表達(dá)水平〔35〕；抑制黑質(zhì)DA能神經(jīng)元的放電頻率和爆發(fā)式放電活動(dòng)，改善黑質(zhì)-紋狀體DA能通路的功能〔47〕。上述結(jié)果可能均與運(yùn)動(dòng)的神經(jīng)保護(hù)作用調(diào)節(jié)了黑質(zhì)-紋狀體DA能神經(jīng)傳遞過程有關(guān)。有關(guān)運(yùn)動(dòng)防治PD的神經(jīng)可塑性機(jī)制也有相關(guān)文獻(xiàn)報(bào)道，他們大多數(shù)集中在紋狀體MSNs的突觸可塑性方面。Toy等〔48〕的研究表明，持續(xù)6周的遞增負(fù)荷跑臺(tái)運(yùn)動(dòng)可明顯增加MPTP 小鼠紋狀體MSNs突觸后致密物和突觸囊泡的數(shù)量，并明顯增加MSNs樹突棘分支和密度；本實(shí)驗(yàn)室前期研究也發(fā)現(xiàn)，4周跑臺(tái)運(yùn)動(dòng)干預(yù)，明顯減少了PD模型大鼠紋狀體MSNs樹突棘的脫落〔49〕；降低了紋狀體Glu能突觸活性，抑制了皮層-紋狀體Glu能通路的過度興奮，顯著改善了皮層-紋狀體突觸可塑性〔50〕。

眾所周知，咖啡因是一種中樞神經(jīng)系統(tǒng)興奮劑〔51〕，補(bǔ)充咖啡因能夠促進(jìn)高強(qiáng)度運(yùn)動(dòng)能力和運(yùn)動(dòng)表現(xiàn)力〔52〕，縮短大強(qiáng)度運(yùn)動(dòng)后疲勞的恢復(fù)時(shí)間，有利于提高耐力和抗疲勞能力〔53〕。有研究發(fā)現(xiàn)，咖啡因攝取量與PD發(fā)病呈負(fù)相關(guān)〔54〕；6-OHDA模型大鼠給予兩周低劑量咖啡因治療后自主行為活動(dòng)明顯改善，A2AR拮抗劑也有類似的作用效果〔55〕。目前的研究已經(jīng)證實(shí)，咖啡因是一種非特異性腺苷受體拮抗劑，進(jìn)入體內(nèi)后通過抑制紋狀體A2AR的活性，下調(diào)蒼白球外側(cè)部GABA水平，使丘腦底核的興奮性減弱，對(duì)皮層起到去抑制作用，從而達(dá)到改善PD大鼠行為功能和運(yùn)動(dòng)障礙的效果〔56〕。由此推測，運(yùn)動(dòng)改善PD大鼠行為功能障礙的機(jī)制可能是通過紋狀體D2-MSNs胞膜上的A2AR/D2DR相互作用，抑制A2AR或激活D2DR的活性，糾正PD狀態(tài)下紋狀體-蒼白球通路GABA神經(jīng)元的過度興奮，抑制間接通路的活性，調(diào)節(jié)了基底神經(jīng)節(jié)功能紊亂。但目前仍缺乏直接的實(shí)驗(yàn)證據(jù)，有待進(jìn)一步研究考證。

4 小 結(jié)

A2AR/D2DR共存于基底神經(jīng)節(jié)紋狀體D2-MSNs突觸后膜，通過變構(gòu)與配體結(jié)合或與其他受體相互作用形成多聚體聚合物調(diào)節(jié)突觸后神經(jīng)元功能。A2AR拮抗D2DR的表達(dá)是導(dǎo)致間接通路過度激活的重要原因，這與PD狀態(tài)下運(yùn)動(dòng)障礙發(fā)生密切相關(guān)。運(yùn)動(dòng)可能通過抑制A2AR或激活D2DR的活性，糾正PD狀態(tài)下紋狀體-蒼白球通路GABA神經(jīng)元的過度激活，調(diào)節(jié)間接通路的興奮性和基底神經(jīng)節(jié)直接與間接通路的平衡，達(dá)到改善PD病人行為功能障礙的治療效果。A2AR可能成為今后運(yùn)動(dòng)干預(yù)防治PD研究的新靶向。

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〔2016-02-04修回〕

(編輯 李相軍)

國家自然科學(xué)基金資助項(xiàng)目(31571221)；北京市自然科學(xué)基金資助項(xiàng)目(5142012)

劉曉莉(1958-)，女，博士，教授，博士生導(dǎo)師，主要從事體育保健與運(yùn)動(dòng)康復(fù)研究。

王 弘(1991-)，女，在讀碩士，主要從事運(yùn)動(dòng)人體科學(xué)研究。

R322.8

A

1005-9202(2017)01-0222-05；

10.3969/j.issn.1005-9202.2017.01.098