運動干預改善帕金森病運動癥狀及可能機制的研究進展*

陳 平， 喬德才， 劉曉莉

(1北京師范大學體育與運動學院， 北京 100875； 2呂梁學院體育系， 山西 呂梁 033000 )

帕金森病(Parkinson disease，PD)，又名震顫麻痹(paralysis agitants)，由英國醫(yī)師James Parkinson(1817年)在他的《震顫麻痹分析》(Essayon the shaking palsy)一文中首先描述[1]，被認為是第二大與年齡相關(guān)的、以中腦黑質(zhì)多巴胺(dopamine，DA)能神經(jīng)元丟失導致紋狀體DA遞質(zhì)減少為特征的漸進性、不可逆轉(zhuǎn)性神經(jīng)功能障礙性疾病[2-3]，堪稱是繼腫瘤和心腦血管病之后中老年的“第三殺手”[4]。PD的神經(jīng)病理學特征為中腦黑質(zhì)DA能神經(jīng)元變性丟失和殘存神經(jīng)元胞漿內(nèi)嗜酸性包涵體路易小體(包含α-突觸核蛋白和泛素化)形成，導致黑質(zhì)-紋狀體通路DA釋放減少(圖1[5])，從而出現(xiàn)以運動功能障礙(如運動遲緩、肌肉僵直、靜止性震顫、步態(tài)障礙和身體姿勢不穩(wěn)等)為主要特征的臨床綜合征，最終導致患者日常生活活動困難和生活質(zhì)量下降[6]?？捎玫乃幚韺W和神經(jīng)調(diào)節(jié)方法雖然緩解了PD的運動障礙癥狀，但到目前為止，臨床上尚無有效手段能夠治愈、阻止或者延緩PD的進展。流行病學調(diào)查發(fā)現(xiàn)，長期的身體活動與PD的低發(fā)病率呈高度相關(guān)[7]；運動具有改善PD患者運動癥狀的潛力，已被廣泛應(yīng)用于PD臨床康復治療[8-9]。本文就運動干預改善帕金森病運動癥狀及可能機制進行綜述。

1 運動對PD運動癥狀的改善

PD的主要特征是步態(tài)障礙和平衡能力的喪失。在PD中，運動干預通常被用來改善PD患者的步態(tài)和平衡功能障礙。

步態(tài)障礙包括速度和步長的下降以及步幅長度的增加，并可能影響到個體的生活質(zhì)量[10]。跑臺訓練由于易于調(diào)整速度(和坡度)，從而增加步態(tài)練習的強度和挑戰(zhàn)性而通常被用來改善PD患者的步態(tài)能力。大量研究結(jié)果表明，輕度至中度的PD患者經(jīng)跑臺訓練后可顯著改善他們的步態(tài)表現(xiàn)，包括步速、步長、節(jié)奏、姿勢穩(wěn)定性、步態(tài)節(jié)律性和關(guān)節(jié)移動度[11-14]。另外，跑臺訓練的這種效益不僅體現(xiàn)在運動完成后的即刻，甚至在停止訓練后也長期(持續(xù)幾個月)保留[15-16]。但也有一些研究表明，跑臺訓練對PD患者步態(tài)能力沒有實質(zhì)性的改善[17]，這可能是由于疾病的嚴重程度不同所導致的。除了跑臺訓練外，Arcolin等[18]研究表明，PD患者在進行24個月(每周2次)的漸進性抗阻訓練干預后，患者的步態(tài)速度、節(jié)奏、跖屈強度和步長均顯著升高；分別對PD患者進行3周循環(huán)測功儀訓練(cycle ergometer trai-ning)和12周的主動輔助強迫運動訓練后， PD患者的步態(tài)參數(shù)得到顯著的改善，表現(xiàn)為步速、步長、擺動相和單支撐相顯著升高，足偏角及步寬顯著降低，6 min步行測試、平衡測試及起立-行走時間測試得分均顯著提高[19-20]；對PD患者進行水中體育鍛煉后，步態(tài)參數(shù)顯著改善，表現(xiàn)為步行速度、步長、單跨步時間和單雙腳支撐時間均顯著提高[21-22]；Allen等[23]研究表明，6周氣功鍛煉對PD患者步態(tài)功能有益，表現(xiàn)為鍛煉后可使PD患者步幅長度、步速顯著增加，步態(tài)變異性顯著改善，特別是單跨步時間變異性顯著降低。

Figure 1. Diagrams of basal ganglia-thalamic cortex loop regulation at physiological and PD status[5].

圖1生理和PD狀態(tài)下基底神經(jīng)節(jié)-丘腦皮層環(huán)路調(diào)控模式圖[5]

平衡功能障礙是導致PD個體致殘率增加及健康相關(guān)的生活質(zhì)量和生存率降低的主要原因，許多鍛煉方式旨在改善PD患者的平衡能力[24]。研究表明，太極拳將緩慢的移動控制、力量、多方向運動，以及需要認知注意的連續(xù)復雜動作自然地結(jié)合到了一起，通過身體重量移動來控制最大運動期間的重心從而專注于對動態(tài)姿勢的控制[25]。大量隨機對照試驗研究表明，太極拳訓練對PD患者姿勢控制具有有益的影響，并得到了社區(qū)PD患者的關(guān)注[26]。研究表明，太極拳訓練可有效減輕輕度至中度PD患者肢體僵硬程度，改善肢體靈活性，使下肢力量和步幅顯著增加，行走速度加快，跌倒頻率顯著降低，有效改善患者的步態(tài)和平衡功能，且這些有益的效用至少保留2個月[27]。

同傳統(tǒng)的運動干預方式相比，探戈、華爾茲和狐步舞對PD患者的平衡、步態(tài)和耐力均具有顯著的促進作用。一項基于社區(qū)的隨機對照研究發(fā)現(xiàn)，同對照組相比，12個月的探戈訓練導致PD患者疾病的嚴重程度(統(tǒng)一帕金森病評定量表得分)顯著降低，如日常生活活動、運動遲緩、肌肉僵直、震顫、平衡障礙和雙任務(wù)行走均得到顯著改善；此外，隨訪時對照組具有更多的凍結(jié)步態(tài)發(fā)生，6 min步行測試惡化，但舞蹈組保持穩(wěn)定[28]；另有研究表明，10周的舞蹈訓練可使PD患者平衡和步態(tài)障礙得到改善，具體表現(xiàn)為起立-步行計時測試和6 min步行測試得分均顯著提高[29]。

拳擊是包含多向運動的動態(tài)平衡活動。研究表明，12周的拳擊訓練可使輕度PD患者的平衡、步態(tài)、日常生活活動和生活質(zhì)量顯著改善；較長時間(36周)的拳擊訓練可使中度至重度PD患者顯示最大的訓練效果[30]。Konerth等[31]研究表明，10周平衡訓練可顯著改善PD患者的肌肉力量和平衡功能，表現(xiàn)為平衡測試得分顯著提高，跌倒次數(shù)顯著降低，跌倒?jié)摲?latency to fall)顯著增加，膝關(guān)節(jié)伸展/屈曲及踝關(guān)節(jié)伸展力量均顯著增加，且這種效果至少持續(xù)4周。此外，身體活動與上下樓梯或在不使用手的情況下從無扶手椅子上站立起來所需的時間的減少以及總步行距離的增加顯著相關(guān)[32]；8周多維平衡訓練可使PD患者平衡功能和雙任務(wù)步態(tài)表現(xiàn)顯著改善，表現(xiàn)為步態(tài)速度、平衡評價系統(tǒng)測驗總分及各項得分、雙重任務(wù)起立-行走計時測試得分和特定活動平衡信心量表得分均顯著提高，且這種有益效用可持續(xù)到12周以后[33]。

綜合以上研究，運動/身體鍛煉對改善PD患者運動癥狀或減緩癥狀的發(fā)展具有非常積極的作用。但是，后續(xù)的隨訪評估研究卻很少，并且哪種運動方式最適合PD患者也不清楚。因此，各種運動方式之間的對比和運動帶來的長期效益仍然需要系統(tǒng)的研究和更多的探索。

2 運動干預改善PD運動癥狀的可能機制

盡管運動/身體鍛煉改善PD運動功能障礙或減緩PD癥狀發(fā)展的結(jié)論已在臨床和基礎(chǔ)研究中都得到了證實，但其潛在機制卻存在不同的解釋。目前主要有以下兩種觀點：即運動的神經(jīng)保護性作用和運動的神經(jīng)可塑性作用。

2.1運動的神經(jīng)保護性作用

2.1.1運動的抗氧化應(yīng)激作用 氧化應(yīng)激(Oxidative stress，OS)是一種以氧化組分含量顯著增加為特征的級聯(lián)反應(yīng)。氧化應(yīng)激假說推測細胞高活性氧的產(chǎn)生和抗氧化系統(tǒng)失衡進而導致PD(圖2[34])。

Figure 2. Reactive oxygen species and the pathogenesis of Parkinson’s disease[34]. A： the production of reactive oxygen species； B： the imbalance between production and elimination of reactive oxygen species.

圖2活性氧簇和PD的發(fā)病機制[34]

研究表明，PD狀態(tài)下，中腦黑質(zhì)DA能神經(jīng)元處于高氧化應(yīng)激狀態(tài)，脂質(zhì)、蛋白質(zhì)和DNA氧化的副產(chǎn)物升高，抗氧化系統(tǒng)的代償性增加[35]。PD患者黑質(zhì)脂質(zhì)氧化的標記物丙二醛和脂質(zhì)過氧化的水平較正常人高10倍[36]。在細胞水平，PD患者黑質(zhì)殘存的DA能神經(jīng)元內(nèi)脂質(zhì)過氧化的主要產(chǎn)物4-羥基壬烯醛的表達量較正常的對照個體顯著升高[37]。PD患者黑質(zhì)DA能神經(jīng)元DNA和RNA氧化的標記物8-羥基脫氧尿苷顯著增加[38]。黑質(zhì)蛋白質(zhì)氧化的標志物蛋白質(zhì)羰基化合物的水平是其它腦區(qū)的2倍。黑質(zhì)中用來清除ROS的抗氧化物質(zhì)如谷胱甘肽(glutathione，GSH)、超氧化物歧化酶(superoxide dismutase，SOD)、谷胱甘肽過氧化物酶(glutathione peroxidase，GPx)和過氧化氫酶(catalase)等均顯著降低，亞鐵離子(Fe2+)濃度顯著增高[39-40]。針對氧化應(yīng)激的抗氧化治療方案是目前治療PD的重要手段之一，且在實驗和臨床中取得了一定的療效。Aguiar等[41]研究表明，6周跑臺訓練可使6-羥多巴胺(6-hydroxydopamine，6-OHDA)誘導的PD小鼠模型黑質(zhì)-紋狀體DA能神經(jīng)元丟失減輕，運動功能改善，表現(xiàn)為黑質(zhì)酪氨酸羥化酶(tyrosine hydroxylase，TH)免疫陽性細胞數(shù)量和紋狀體TH免疫陽性纖維終末含量顯著升高，前肢不對稱性測驗得分和阿撲嗎啡誘導的旋轉(zhuǎn)次數(shù)顯著降低；參與線粒體生物發(fā)生和抗氧化防御酶基因表達水平顯著升高，表現(xiàn)為線粒體轉(zhuǎn)錄因子、NADH脫氫酶Q1α子復合體亞基6、線粒體復合物Ⅰ、核因子E2相關(guān)因子2(nuclear factor E2-related factor 2，Nrf2)和血紅素氧合酶1(heme oxygenase-1，HO-1)mRNA表達水平顯著升高，線粒體復合物1的活性及線粒體復合物與檸檬酸合酶的比率顯著升高，紋狀體亞硝酸鹽的含量顯著降低。Tsou等[42]研究表明，4周跑臺訓練可使MPTP誘導的PD小鼠模型黑質(zhì)-紋狀體DA能神經(jīng)元丟失減輕，抗氧化能力增強，表現(xiàn)為黑質(zhì)TH免疫陽性細胞數(shù)量、紋狀體TH免疫陽性纖維終末含量及黑質(zhì)-紋狀體TH蛋白表達水平顯著升高，紋狀體多巴胺轉(zhuǎn)運體、黑質(zhì)-紋狀體總谷胱甘肽含量以及氧化型谷胱甘肽與總谷胱甘肽的比率顯著升高，黑質(zhì)-紋狀體Nrf2 mRNA表達水平和γ-谷氨酰半胱氨酸連接酶催化亞基(γ-glutamate-cysteine ligase catalytic subunit，γ-GCLC)及HO-1蛋白表達水平顯著升高。Nrf2-抗氧化反應(yīng)元件(antioxidant responsive element，ARE)信號通路是對抗氧化應(yīng)激的一個重要的細胞防御機制。Nrf2-ARE通路強有力地參與了神經(jīng)保護和抗炎癥反應(yīng)。研究表明， Nrf2被ROS激活后，與ARE啟動子序列結(jié)合，從而使ARE包含的基因表達上調(diào)，如醌氧化還原酶1、γ-GCLC、谷胱甘肽S-轉(zhuǎn)移酶、HO-1等[43]。大量研究證據(jù)表明，利用Nrf2小分子誘導劑或Nrf2基因過表達治療對腦缺血或者PD模型具有神經(jīng)保護作用[44]。此外，Nrf2丟失促進MPTP的毒性作用，并能夠使α-突觸核蛋白過表達，加劇DA能神經(jīng)元的丟失[45]。這些研究結(jié)果表明，運動可能通過Nrf2-ARE信號通路調(diào)節(jié)抗氧化酶的表達，從而增強機體抗氧化防御系統(tǒng)功能及自由基清除能力，進而在PD中發(fā)揮神經(jīng)保護作用，見圖3。

2.1.2運動的神經(jīng)營養(yǎng)作用 神經(jīng)營養(yǎng)因子(neurotrophic factors, NTFs) 是機體產(chǎn)生的能夠促進神經(jīng)元發(fā)育和正常生理功能的一類蛋白因子,主要包括腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor，BDNF)、膠質(zhì)細胞源性營養(yǎng)因子(glial cell line-derived neurotrophic factor，GDNF)、腦多巴胺神經(jīng)營養(yǎng)因子(cerebral dopamine neurotrophic factor，CDNF)和神經(jīng)營養(yǎng)因子3(neurotrophin-3，NF-3)等。這些NTFs通過其高親和力的共同受體——原肌球蛋白相關(guān)激酶B(tropomyosin-related kinase B，TrkB)對神經(jīng)元的生長、發(fā)育、分化、存活、凋亡和損傷后修復進行調(diào)節(jié)。

Scalzo等[46]研究表明，PD患者血清BDNF濃度顯著降低；Tajiri 等[47]和Lau 等[48]研究表明，PD動物模型黑質(zhì)DA能神經(jīng)元退行性病變伴隨著BDNF表達的顯著降低；Nam等[49]研究表明，PD患者黑質(zhì)致密區(qū)殘存的DA能神經(jīng)元BDNF mRNA及蛋白表達水平顯著降低，與Howells等[50]和Mogi等[51]對PD患者進行尸檢后發(fā)現(xiàn)黑質(zhì)BDNF水平降低的研究結(jié)果一致。GDNF是近年來發(fā)現(xiàn)的特異性最強的DA能神經(jīng)元營養(yǎng)因子。Ngema等[52]和Yue等[53]研究表明，伴隨著6-OHDA損毀大鼠模型黑質(zhì)DA能神經(jīng)元的損傷，黑質(zhì)紋狀體GDNF和NF-3表達顯著降低。而早期運動干預可使神經(jīng)毒素(MPTP和6-OHDA等)誘導的PD動物模型DA能神經(jīng)元得到保護和修復，這可能是運動通過多途徑增加NTFs的表達實現(xiàn)的。Tajiri等[47]和Lau等[48]研究表明，4周跑臺訓練(5 d/week，30 min/d，11 m/min)或18周遞增負荷跑臺訓練(5 d/week，40 min/d)均可使PD大鼠或小鼠模型黑質(zhì)-紋狀體系統(tǒng)BDNF和GDNF表達顯著增加，紋狀體TH陽性纖維終末及黑質(zhì)致密部TH陽性神經(jīng)元得到顯著保護，運動功能顯著改善。Jang等[54]和Wu等[55]研究表明，跑臺訓練可使PD小鼠模型黑質(zhì)、紋狀體BDNF、GDNF及TrkB表達水平顯著增高，DA能神經(jīng)元丟失顯著降低，行為功能障礙減輕。而BDNF或者GDNF表達降低(或者消除)，TrkB拮抗劑或者TrkB基因敲除可使運動誘導的神經(jīng)保護作用及運動功能改善消失[56-58]。這些研究結(jié)果表明，運動干預可能通過提高NTFs的表達，保護或者減輕神經(jīng)毒素對PD動物模型DA能神經(jīng)元的毒性損傷。其機制可能是增加的NTFs通過與其受體TrkB結(jié)合，引起TrkB自身磷酸化作用增強，進而直接或者間接觸發(fā)胞內(nèi)下游信號傳遞的級聯(lián)反應(yīng)[59]，從而促進DA能神經(jīng)元的存活，見圖3、4。

2.2運動的神經(jīng)可塑性作用 紋狀體DA耗竭引起皮層-紋狀體谷氨酸(glutamate acid，Glu)能通路過度激活，突觸前末梢釋放大量的Glu對突觸后膜產(chǎn)生興奮性毒作用是導致PD狀態(tài)下紋狀體一系列病理改變的原因之一。Glu介導的興奮性毒作用使紋狀體MSNs樹突棘末梢Ca2+超載，表現(xiàn)為紋狀體中型多棘神經(jīng)元樹突棘(medium spiny neurons，MSNs)形態(tài)結(jié)構(gòu)的異常改變(如樹突棘數(shù)量、密度降低和超微結(jié)構(gòu)異常等)以及皮層-紋狀體突觸連接功能的增強。

William等[60]、Toy等[61]和Shin 等[62]研究發(fā)現(xiàn)，4周大強度跑臺訓練可顯著增加PD小鼠模型紋狀體樹突棘的數(shù)量和密度；陳巍等[63]研究發(fā)現(xiàn)，4周中等強度跑臺訓練在顯著增加PD大鼠模型紋狀體MSNs樹突棘數(shù)量和密度的同時，顯著降低紋狀體MSNs不對稱性突觸中穿通型突觸的比例。Kintz等[64]和VanLeeuwen等[65]研究表明，4周大強度跑臺訓練使MPTP小鼠皮層-紋狀體通路突觸前Glu釋放顯著降低，紋狀體MSNs包含GluR2亞基的α-氨基-3-羥基-5-甲基-4-異噁唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid，AMPA)受體蛋白表達、mRNA轉(zhuǎn)錄及其第880位絲氨酸磷酸化程度顯著增高；紋狀體MSNs興奮性突觸后電流的大小和幅度均顯著降低，多胺敏感性內(nèi)向整流喪失；陳巍等[66]研究表明，4周跑臺訓練可使6-OHDA誘導的PD大鼠模型紋狀體Glu濃度降低，紋狀體包含GluR2亞基的AMPA受體表達及MSNs膜上CaV1.3鈣離子通道和相關(guān)蛋白磷酸化水平上調(diào)；劉曉莉等[67]研究發(fā)現(xiàn)，4周中等強度跑臺訓練干預可使PD大鼠模型紋狀體MSNs放電頻率，爆發(fā)式放電神經(jīng)元的比例顯著降低，持續(xù)緊張性電位的發(fā)放顯著減少；紋狀體MSNs對皮層刺激反應(yīng)的閾強度顯著增加，平均放電頻率顯著降低，放電頻率增加的潛伏期顯著延長。提示運動可能引起PD動物模型紋狀體MSNs樹突棘形態(tài)結(jié)構(gòu)及皮層-紋狀體突觸連接的重塑。其機制可能是運動通過增加PD動物模型紋狀體包含GluR2亞基的AMPA受體表達，降低Ca2+內(nèi)流，抑制Ca2+依賴性蛋白酶的激活和胞內(nèi)一系列信號級聯(lián)反應(yīng)的啟動，最終達到降低皮層-紋狀體Glu能通路的過度激活的作用。

Figure 3. The neuroprotective effect of physical exercise in PD.

圖3運動在PD中的神經(jīng)保護作用

Figure 4. Activation of BDNF downstream intracellular signaling pathways[59]. BDNF： brain-derived neurotrophic factor; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; ERK: extracellular signal-regulated kinase; GAB1: GRB-associated binder 1; Ins(1,4,5)P3: inositol-1,4,5-trisphosphate; DAG: triacylglycerol; PKC: protein kinase C; Ca2+/CaM: Ca2+/calmodulin; CaMK: Ca2+/calmodulin-dependent protein kinase.

圖4BDNF激活下游細胞內(nèi)信號通路[59]

此外，位于紋狀體MSNs上的多巴胺1型受體(dopamine type 1 receptor，DA-D1R)和多巴胺2型受體(dopamine type 2 receptor，DA-D2R)是DA的主要靶點并調(diào)節(jié)生理特性和細胞信號。DA-D2R在長時程抑制(long-term depression，LTD)形成過程中起著重要的作用，其作為突觸可塑性的一種形式，涉及到谷氨酸能和多巴胺能神經(jīng)傳遞的整合，從而導致背側(cè)紋狀體運動功能的編碼。在PD動物模型，通過應(yīng)用DA或者DA-D2R激動劑能夠?qū)е翽D運動障礙逆轉(zhuǎn)[68]。陳巍等[69]采用免疫組織化學結(jié)合免疫印跡技術(shù)方法研究表明，4周中等強度跑臺訓練可使6-OHDA大鼠模型紋狀體DA-D2R蛋白表達顯著上調(diào)，運動功能改善；Lindenbach等[70]采用免疫印跡技術(shù)結(jié)合在體正電子發(fā)射計算機斷層顯像技術(shù)(positron emission tomography，PET)研究表明，6周大強度跑臺訓練可使MPTP小鼠模型背側(cè)紋狀體DA-D2R表達顯著升高，運動功能改善。這些研究表明運動還能夠通過增加紋狀體DA-D2R的表達增強DA能信號以及抑制谷氨酸能的興奮性來改變運動皮層和基底神經(jīng)節(jié)的突觸可塑性。

3 結(jié)論和展望

PD已成為全世界日益嚴重的問題。運動/體育鍛煉可以改善輕度至中度PD患者運動功能障礙或減緩癥狀的發(fā)展。建議臨床醫(yī)生應(yīng)將運動視為PD患者特別是輕度至中度PD患者的一種重要輔助或替代療法，以降低與該疾病有關(guān)的風險(例如跌倒)，改善運動功能，并延緩PD的進展。運動對PD晚期以及長期效應(yīng)仍然是未知的。未來的研究需要就運動對PD晚期及長期效應(yīng)進行探討，并將在體檢測運動對PD患者腦中化學物質(zhì)的影響，以便能夠更好地理解運動改善PD癥狀背后潛在的細胞和分子機制。

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