神經(jīng)營養(yǎng)因子介導(dǎo)運(yùn)動的抗抑郁作用

劉文彬，劉微娜，漆正堂

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神經(jīng)營養(yǎng)因子介導(dǎo)運(yùn)動的抗抑郁作用

劉文彬1,2，劉微娜1,2，漆正堂1,2

1.華東師范大學(xué) “青少年健康評價與運(yùn)動干預(yù)”教育部重點(diǎn)實(shí)驗(yàn)室, 上海 200241; 2.華東師范大學(xué) 體育與健康學(xué)院, 上海 200241

神經(jīng)營養(yǎng)因子是對神經(jīng)元的發(fā)育、存活及凋亡發(fā)揮作用的蛋白質(zhì)，因其在神經(jīng)發(fā)育和神經(jīng)可塑性中扮演的重要角色而備受神經(jīng)科學(xué)領(lǐng)域的關(guān)注。抑郁的神經(jīng)營養(yǎng)假說認(rèn)為，抑郁會引起神經(jīng)營養(yǎng)因子表達(dá)水平的改變，抑郁癥患者多種神經(jīng)營養(yǎng)因子的血清水平和腦區(qū)表達(dá)較健康人有明顯差異，提示，神經(jīng)營養(yǎng)因子可能成為新型抑郁癥標(biāo)志物。運(yùn)動可通過改變多種神經(jīng)營養(yǎng)因子的表達(dá)水平，包括神經(jīng)生長因子基因家族、成纖維細(xì)胞生長因子家族、生神經(jīng)細(xì)胞因子家族、膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子家族以及血管內(nèi)皮生長因子和胰島素樣生長因子-1等其他神經(jīng)營養(yǎng)因子，進(jìn)而調(diào)控神經(jīng)可塑性、神經(jīng)發(fā)生、細(xì)胞存活、下丘腦-垂體-腎上腺軸活性、單胺類神經(jīng)遞質(zhì)、中樞炎癥等，從而發(fā)揮其抗抑郁作用。梳理神經(jīng)營養(yǎng)因子介導(dǎo)運(yùn)動抗抑郁的可能機(jī)制，這將有助于篩選出“外周營養(yǎng)因子”作為抑郁癥液體活檢、運(yùn)動干預(yù)的生物標(biāo)記，為抑郁癥的研究和治療提供更多可能性。

神經(jīng)營養(yǎng)因子；抑郁；運(yùn)動干預(yù)；介導(dǎo)機(jī)制

自20世紀(jì)80年代以來，人們發(fā)現(xiàn)不同類型生長因子對神經(jīng)元的發(fā)育及生長發(fā)揮調(diào)節(jié)支持作用，這些具有神經(jīng)營養(yǎng)作用的物質(zhì)被統(tǒng)稱為神經(jīng)營養(yǎng)因子（neurotrophic factors, NTFs），包括神經(jīng)生長因子基因家族（nerve growth factor gene family）、成纖維細(xì)胞生長因子家族（fibroblast growth factor family）、生神經(jīng)細(xì)胞因子家族（neuropoietic cytokine family）、膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子家族（gliar cell line-derived neurotriphic factor family）以及血管內(nèi)皮生長因子（vascular endothelial growth factor，VEGF）、胰島素樣生長因子-1（insulin-likegrowthfactor1，IGF-1）等其他神經(jīng)營養(yǎng)因子。根據(jù)Duman提出的“神經(jīng)營養(yǎng)假說”[36]，某些NTFs可改變由抑郁導(dǎo)致的神經(jīng)元萎縮或凋亡，且抗抑郁治療可逆轉(zhuǎn)抑郁引發(fā)的NTFs血清濃度及其表達(dá)發(fā)生的改變，因此，某些NTFs一定程度上可被視為抑郁癥的外周標(biāo)志物。近年來，運(yùn)動療法因其療效顯著，無毒副作用，可同時降低其他疾病發(fā)病率等優(yōu)勢在抑郁治療領(lǐng)域中備受青睞。研究發(fā)現(xiàn)，運(yùn)動可使某些NTFs的濃度和表達(dá)發(fā)生改變，提示，NTFs可能介導(dǎo)了運(yùn)動的抗抑郁作用。本文主要對與抑郁癥密切相關(guān)的NTFs及其介導(dǎo)運(yùn)動抗抑郁的可能機(jī)制作一綜述。

1 神經(jīng)生長因子基因家族

神經(jīng)生長因子基因家族在胚胎發(fā)育期參與建立神經(jīng)系統(tǒng)，保護(hù)和修復(fù)受損神經(jīng)元并促進(jìn)其生長，對神經(jīng)細(xì)胞的存活、生長、發(fā)育、分化及新陳代謝等都具有重要調(diào)控作用。該家族目前已知成員除神經(jīng)生長因子（nerve growth factor，NGF）外，還有腦源性神經(jīng)營養(yǎng)因子（brain derived neurotrophic factor，BDNF）、神經(jīng)營養(yǎng)素-3（neurotrophin-3，NT-3）、神經(jīng)營養(yǎng)素-4/5（neurotrophin-4/5，NT-4/5）等。

1.1 神經(jīng)生長因子（NGF）

NGF是一類促進(jìn)神經(jīng)生長的多肽，除可維持神經(jīng)元生長存活外，還可介導(dǎo)突觸形態(tài)可塑性。臨床研究顯示，抑郁患者血清NGF水平明顯低于對照組[104]。抑郁癥患者的抗抑郁效力與NGF基因多態(tài)性相關(guān)，NGF的DNA序列類型與抑郁治療后的緩解程度有關(guān)[138]。動物研究發(fā)現(xiàn)，應(yīng)激小鼠NGF的mRNA水平降低[56]，抑郁大鼠NGF的mRNA水平同樣降低，且表現(xiàn)為海馬和頂葉皮質(zhì)神經(jīng)元受損，這為NGF通過神經(jīng)元保護(hù)而防治抑郁提供了依據(jù)[5]。NGF可調(diào)節(jié)大量微小RNA（microRNAs，miRs）的表達(dá)，miRs又可調(diào)控涉及神經(jīng)元發(fā)育和疾病信號通路的蛋白質(zhì)。在大鼠腎上腺嗜鉻細(xì)胞瘤細(xì)胞（pheochromocytoma cells，PC12）中，NGF顯著上調(diào)miR-21水平，并引發(fā)絲裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）和蛋白激酶B（protein kinase B，PKB即Akt）通路磷酸化，而MAPK和Akt是磷脂酰肌醇激酶（phosphoinositide 3-kinase，PI3K）信號的關(guān)鍵酶，因此，NGF可能通過miR-21/PI3k/MAPK/Akt通路，促進(jìn)神經(jīng)元分化并實(shí)現(xiàn)其對神經(jīng)退行性疾病的調(diào)控[88]。

動物研究發(fā)現(xiàn)，自主跑輪運(yùn)動可緩解社會隔離模型誘導(dǎo)的海馬NGF濃度減少，并降低大鼠的焦慮分?jǐn)?shù)[89]；游泳運(yùn)動可改善應(yīng)激大鼠海馬NGF水平的下調(diào)[61]。長期跑臺運(yùn)動通過拮抗下丘腦-垂體-腎上腺軸（hypothalamic-pituitary-adrenal axis，HPA軸）功能亢進(jìn)，減少皮質(zhì)醇分泌，并使得抑郁大鼠海馬NGF表達(dá)增強(qiáng)，從而阻止氧化應(yīng)激引起的中樞神經(jīng)元死亡[7]。跑臺運(yùn)動可升高抑郁大鼠NGF水平，NGF可能通過突觸素I（synapsin I，SYN I）增加中縫核5-羥色胺（5-hydroxytryptamine，5-HT）細(xì)胞數(shù)目，近而增加海馬神經(jīng)元存活率[57]。抑郁發(fā)病與中樞神經(jīng)元的凋亡密切相關(guān)，因此，運(yùn)動可能通過調(diào)控NGF進(jìn)而影響突觸及神經(jīng)元的生長存活，以實(shí)現(xiàn)對抑郁癥的改善和治療。

1.2 腦源性神經(jīng)營養(yǎng)因子（BDNF）

BDNF是一類可促進(jìn)維持神經(jīng)元生長、存活及功能的活性蛋白因子，其廣泛分布于海馬等中樞神經(jīng)部位，通過酪氨酸激酶受體B（tyrosine kinase receptor B，TrkB）激活信號傳導(dǎo)。抑郁癥患者血清BDNF水平低于正常人，且血清BDNF水平與抑郁嚴(yán)重程度可能呈負(fù)相關(guān)[63]。抑郁癥患者血清組織型纖溶酶原激活劑（tissue-type plasminogen activator，tPA）與BDNF前體（proBDNF）比率降低，tPA-BDNF通路可能與抑郁機(jī)制有關(guān)，因此，將tPA、BDNF、TrkB、proBDNF及p75神經(jīng)營養(yǎng)因子受體（p75 neurotrophin receptor，p75NTR）相結(jié)合，將可能為重度抑郁癥提供新的生物診斷標(biāo)準(zhǔn)[60]，且tPA/BDNF通路中的基因變異可能在卒后抑郁的調(diào)控機(jī)制中發(fā)揮關(guān)鍵作用[79]。BDNF和ProBDNF二者間特別的修飾機(jī)制使其在抑郁中發(fā)揮完全相反的作用[87]。慢性應(yīng)激引起海馬BDNF/proBDNF比率降低，導(dǎo)致海馬CA1區(qū)錐體神經(jīng)元樹突棘密度減少，并伴隨胞質(zhì)內(nèi)蛋白kalirin-7、突觸后密度蛋白-95（postsynaptic density-95，PSD95）和N-甲基-D-天門冬氨酸（N-methy-D-aspartate，NMDA）受體亞單位NR2B水平減少，從而誘發(fā)抑郁行為[101]。氯胺酮可通過阻斷NMDA受體活動提高BDNF水平，從而發(fā)揮抗抑郁療效[17]。環(huán)磷酸腺苷（cyclic adenosine monophosphate，cAMP）和核因子κB（nuclear factor-kappa B，NF-κB）分別在上下游參與BDNF介導(dǎo)的抑郁發(fā)病機(jī)制[24, 29]。此外，BDNF與TrkB結(jié)合后可能通過PI3K/AKT/糖原合成酶激酶3β（glycogen synthase kinase 3β，GSK-3β）/β-鏈蛋白（β-catenin）或細(xì)胞外信號調(diào)節(jié)激酶（extracellular signal-regulated kinase，ERK）/核糖體S6激酶（ribosomal S6 kinase，RSK）/環(huán)磷腺苷效應(yīng)元件結(jié)合蛋白（cAMP-response element binding protein，CREB）通路，實(shí)現(xiàn)對細(xì)胞的調(diào)控從而改善抑郁[29]。

BDNF可能是對運(yùn)動調(diào)控最為敏感的神經(jīng)營養(yǎng)因子。運(yùn)動可增加抑郁癥患者血清BDNF濃度[65]，也可提高抑郁大鼠血清和海馬的BDNF水平，且運(yùn)動的形式和強(qiáng)度均影響B(tài)DNF水平的變化程度[119]。BDNF與抑郁發(fā)病的炎癥標(biāo)志物，如巨噬細(xì)胞移動抑制因子（macrophage migration inhibitory factor，MIF）和白介素-6（interleukin-6，IL-6）等存在相關(guān)性[37]。Ⅲ型纖維連接蛋白域蛋白5（fibronectin type III domain-containing protein5，F(xiàn)NDC5）是鳶尾素分泌的肌肉因子，過氧化物酶體增殖物活化受體γ共激活因子-1α（peroxisome proliferator-activated receptor-γ coactivator-1α，PGC-1α）是重要的代謝調(diào)節(jié)因子，研究表明，運(yùn)動可能通過PGC-1α/FNDC5/BDNF而影響神經(jīng)元的存活、分化及可塑性[134]。運(yùn)動可緩解卵巢摘除大鼠的抑郁行為，可能是因?yàn)锽DNF導(dǎo)致血清中雌二醇水平增加[81]。運(yùn)動還阻止了干擾素-α（interferon-α，IFN-α）誘導(dǎo)的海馬和前額葉皮質(zhì)BDNF表達(dá)的減少，進(jìn)而防止IFN-α誘發(fā)的情感和認(rèn)知功能障礙[22]。運(yùn)動還可通過增加海馬中酮體的累積，抑制組蛋白去乙?；?/3（histone deacetylase，HDAC2/3）的活性，從而促進(jìn)大腦BDNF的表達(dá)，這一過程涉及酮體由肝臟到海馬的代謝轉(zhuǎn)運(yùn)過程，也反映出運(yùn)動介導(dǎo)神經(jīng)營養(yǎng)因子對抑郁的調(diào)控更多是基于代謝層面的[114]。此外，運(yùn)動可激活糖皮質(zhì)激素反應(yīng)從而提高情緒記憶，這一影響由BDNF Val66Met多態(tài)性調(diào)節(jié)[66]。運(yùn)動也可在BDNF啟動子IV這個區(qū)域刺激DNA去甲基化，并提高活化甲基CPG結(jié)合蛋白2（methyl-CpG-binding protein 2，MeCP2），進(jìn)而增加BDNF的mRNA及蛋白水平，起到緩解抑郁的作用[49]。整體而言，BDNF在運(yùn)動抗抑郁領(lǐng)域的研究較為成熟，未來研究可考慮建立BDNF與抑郁程度的具體量化關(guān)系。

1.3 神經(jīng)營養(yǎng)素（neurotrophin，NT）

NT-3、NT-4/5是神經(jīng)元細(xì)胞發(fā)育、存活以及可塑性的關(guān)鍵調(diào)控分子，它們的活動涉及大量相關(guān)基因的轉(zhuǎn)錄和翻譯表達(dá)水平。雙相情感障礙（bipolar disorder，BD）患者血清NT-3和NT-4/5水平升高，這種增加僅存在于BD患者抑郁狀態(tài)下，提示，BD患者NT-3和NT-4/5水平表現(xiàn)為病程狀態(tài)依賴式增加[126]。NT-3可調(diào)節(jié)主要神經(jīng)遞質(zhì)如5-HT、多巴胺（dopamine，DA）和去甲腎上腺素（norepinephrine，NE）等的水平，從而發(fā)揮抗抑郁作用[91]。短期束縛應(yīng)激可增加藍(lán)斑核NE能神經(jīng)元NT-3水平，而抗抑郁治療可降低其水平[115]。與此不同，長期束縛或社會挫敗應(yīng)激下調(diào)小鼠海馬和前額皮質(zhì)的NT-3水平，但在紋狀體中其卻表現(xiàn)為上調(diào)；NE轉(zhuǎn)運(yùn)蛋白基因敲除小鼠卻表現(xiàn)為大腦NT-3水平的改變以及對應(yīng)激的耐受，表明，NT-3可能通過NE激活通路參與情緒調(diào)控[54]。動物研究還發(fā)現(xiàn)，干擾素-β可能作為上游調(diào)控因子，通過上調(diào)被刪節(jié)的TrkC-T1受體表達(dá)抑制NT-3信號[31]。綜上，NT與抑郁之間存在一定關(guān)系，但目前相關(guān)研究較少且呈現(xiàn)出不同結(jié)果，因此，還需要進(jìn)一步明確NT分子在抑郁發(fā)病進(jìn)程中是如何發(fā)揮作用，以及發(fā)揮了怎樣的作用。

鋰（Li）可上調(diào)大腦NT-3水平，影響抑郁癥、肌萎縮側(cè)索硬化癥等多種神經(jīng)退行性疾病的發(fā)病進(jìn)程，提示，NT-3不僅和抑郁相關(guān)，也與運(yùn)動神經(jīng)元存在一定聯(lián)系[143]。自主運(yùn)動誘導(dǎo)的NT-3及其受體TrkC上調(diào)是脊髓損傷的重要恢復(fù)途徑[140]。意向性運(yùn)動療法可增加缺血腦組織中NT-3和海馬軸突膜蛋白（growth-associated protein-43，GAP-43）的表達(dá)，且二者呈正相關(guān)，鑒于NT分子的神經(jīng)營養(yǎng)功能及GAP-43在神經(jīng)元生長發(fā)育過程中所發(fā)揮的作用，推斷NT-3可能是運(yùn)動調(diào)控抑郁的重要中介分子[1]。研究還發(fā)現(xiàn)，運(yùn)動可改善慢性廣泛性疼痛模型動物的痛覺缺失，并上調(diào)肌肉中NT-3水平，肌肉中的NT-3可通過血液進(jìn)入大腦從而發(fā)揮對抑郁的介導(dǎo)作用[112]。此外，運(yùn)動還可上調(diào)腦缺血大鼠模型對側(cè)半球中NT-4及其受體TrkB的水平[28]。目前，NT分子在運(yùn)動抗抑郁中可能存在的Crosstalk尚不清楚，因此，在未來研究中，以NT-3、NT-4/5為代表的NT分子在運(yùn)動抗抑郁的相關(guān)研究中將有望成為新的重要靶點(diǎn)。

2 成纖維細(xì)胞生長因子家族

成纖維細(xì)胞生長因子（fibroblast growth factor，F(xiàn)GF）是具有廣泛生物學(xué)活性的一類多肽，參與細(xì)胞的增殖、分化和遷移，并可改善新陳代謝。迄今為止，已有20多種FGF被發(fā)現(xiàn)，其中大多數(shù)FGF通過與細(xì)胞表面的酪氨酸激酶受體結(jié)合，激活相關(guān)通路向細(xì)胞內(nèi)傳遞信號，從而營養(yǎng)修復(fù)神經(jīng)細(xì)胞、參與血管發(fā)生和調(diào)節(jié)血液循環(huán)，對中樞和周圍神經(jīng)系統(tǒng)發(fā)揮一定的積極效應(yīng)。急性社會應(yīng)激下FGF家族分子水平的下調(diào)與抑郁癥患者死后FGF分子下調(diào)的結(jié)果完全一致，表明，F(xiàn)GF家族分子對抑郁治療具有重要的研究意義。

2.1 成纖維細(xì)胞生長因子2（FGF2）

FGF2不但參與血管生成，還可促進(jìn)神經(jīng)細(xì)胞及組織的損傷修復(fù)和營養(yǎng)保護(hù)。臨床研究顯示，抑郁癥患者前額皮質(zhì)和海馬FGF2表達(dá)降低，且海馬FGF2神經(jīng)元數(shù)量減少[128]。尸檢結(jié)果進(jìn)一步表明，抑郁癥患者海馬CA1、CA4和齒狀回區(qū)域的FGF2水平均降低，而BD和精神分裂癥患者的FGF2水平僅在CA4區(qū)降低，在CA1和齒狀回區(qū)域其表現(xiàn)為升高[45]。慢性抗抑郁藥的治療可增加大腦皮質(zhì)神經(jīng)元、海馬神經(jīng)元以及海馬星形膠質(zhì)細(xì)胞的FGF2免疫活性，并增加大腦皮質(zhì)神經(jīng)元和海馬神經(jīng)元FGF結(jié)合蛋白的免疫活性[11]。動物研究也發(fā)現(xiàn)，F(xiàn)GF2水平與小鼠抑郁程度相關(guān)，外源性注射FGF2可改善抑郁癥狀[4]。應(yīng)激小鼠海馬神經(jīng)營養(yǎng)因子α1（neurotrophic factor-α1，NF-α1）表達(dá)上調(diào)，且通過提高FGF2介導(dǎo)的神經(jīng)發(fā)生，阻止抑郁行為出現(xiàn)，NF-α1通過ERK-Sp1信號激活FGF2，羅格列酮在海馬神經(jīng)元中以NF-α1依賴方式上調(diào)FGF2表達(dá)[27]。FGF2敲除小鼠焦慮增強(qiáng)，同時其海馬腎上腺皮質(zhì)激素受體表達(dá)減少，且HPA軸活動增加[110]。AKT和ERK信號對FGF2的神經(jīng)保護(hù)作用是必需的[26]。外源性FGF2注射可阻止神經(jīng)炎癥導(dǎo)致的ERK1/2磷酸化減少，逆轉(zhuǎn)由神經(jīng)炎癥誘發(fā)的抑郁行為和海馬神經(jīng)發(fā)生受損，提示，F(xiàn)GF2-ERK1/2通路介導(dǎo)了抑郁機(jī)制[120]。大腦皮質(zhì)FGF2缺乏會引起鳥苷酸轉(zhuǎn)化因子Arhgef6及其下游靶點(diǎn)調(diào)節(jié)異常，并伴隨神經(jīng)突生長和樹突棘形態(tài)改變，進(jìn)而影響大腦神經(jīng)系統(tǒng)功能[16]。綜上，NF-α1/ERK-Sp1可能是FGF2抗抑郁機(jī)制的上游信號，激活FGF2后可能通過影響ERK1/2和AKT、Arhgef6及其下游靶點(diǎn)等發(fā)揮抗抑郁作用。

2.2 成纖維細(xì)胞生長因子9（FGF9）

FGF9主要分布于神經(jīng)元中，對神經(jīng)系統(tǒng)的生長發(fā)育起到重要的神經(jīng)營養(yǎng)作用。FGF9功能紊亂可能介導(dǎo)了多種神經(jīng)系統(tǒng)疾病，如阿爾茲海默癥（Alzheimer disease，AD）和肌萎縮側(cè)索硬化癥（Amyotrophic lateral sclerosis，ALS）[42]。目前，F(xiàn)GF9與抑郁的相關(guān)研究較少，有研究表明，F(xiàn)GF9可能作為抑郁的負(fù)調(diào)控因子與FGF2發(fā)揮拮抗作用[38]。抑郁癥患者海馬FGF9表達(dá)上調(diào)，這與尸檢結(jié)果一致，且FGF9與FGF2和FGF受體（FGFR1、FGFR2、FGFR3）的表達(dá)呈負(fù)相關(guān)[10]。FGF9在大腦皮質(zhì)干細(xì)胞中的下調(diào)會縮小增殖的星形池，最終減少星型膠質(zhì)細(xì)胞的產(chǎn)生[39]。健康小鼠注射FGF9后會出現(xiàn)焦慮或抑郁行為，其海馬組織FGF9的高水平在情緒焦慮障礙的發(fā)生發(fā)展中發(fā)揮重要作用，而FGF9敲除可減少焦慮行為[10]。然而，也有研究在抑郁小鼠的海馬中檢測到FGF9的下調(diào)[6]，因此，F(xiàn)GF9究竟是抑郁行為的誘發(fā)因子還是保護(hù)因子仍然存在爭議。FGF9的Y162C突變會負(fù)向調(diào)控小鼠的信息處理及社會記憶感知產(chǎn)生，暗示，F(xiàn)GF9基因改變可能會增加神經(jīng)精神疾病發(fā)病的敏感性[44]。皮質(zhì)醇處理可上調(diào)人體腦組織的FGF9水平并下調(diào)FGF2水平[109]，另外，糖皮質(zhì)激素作用下的FGF/FGFR/Akt/GSK3β通路紊亂可能是介導(dǎo)抑郁的潛在機(jī)制[6]。FGF9在神經(jīng)精神疾病中的分子機(jī)制研究有限，因此，未來可聚焦于FGF9對細(xì)胞的影響，對神經(jīng)遞質(zhì)及相關(guān)分子網(wǎng)絡(luò)的調(diào)節(jié)等方向。

2.3 成纖維細(xì)胞生長因子22（FGF22）

FGF22與腦發(fā)育、突觸形成以及神經(jīng)發(fā)生等有關(guān)，是海馬發(fā)育中興奮性突觸的決定因素，而海馬是抑郁機(jī)制的重要腦區(qū)。抑郁癥患者血清FGF22降低，且FGF22水平與IL-1β水平呈負(fù)相關(guān)；應(yīng)激大鼠側(cè)腦室注射FGF22后，其海馬IL-1β表達(dá)減少，且海馬細(xì)胞凋亡率也得到改善，這意味著FGF22在緩解抑郁過程中發(fā)揮重要作用，并可能由IL-1β表達(dá)下調(diào)所介導(dǎo)[137]。FGF22敲除小鼠表現(xiàn)出抑郁癥狀，但并未出現(xiàn)焦慮、認(rèn)知及運(yùn)動方面的差異，表明，F(xiàn)GF22與抑郁有關(guān)，也意味著在大腦特定腦區(qū)中激活FGF22，用于治療或減少以應(yīng)激和情緒反應(yīng)為主的疾病患病風(fēng)險（如抑郁癥等）有望成為可能[132]。鑒于FGF22是一種針對海馬CA3遠(yuǎn)端區(qū)域的目標(biāo)派生信號，F(xiàn)GF22敲除鼠突觸小泡密度的減少，可作為對CA3區(qū)網(wǎng)絡(luò)活動變化的適應(yīng)以及體內(nèi)突觸釋放率和體外短期抑郁強(qiáng)度的長期調(diào)節(jié)器[95]。此外，F(xiàn)GF22還可調(diào)節(jié)興奮性突觸前末端組織，F(xiàn)GF22在CA3椎體神經(jīng)元中的表達(dá)失衡或缺乏都會影響突觸間的平衡，進(jìn)而導(dǎo)致多種神經(jīng)系統(tǒng)障礙（如自閉癥和精神分裂癥）的發(fā)生[122]。FGF22信號可反饋性誘導(dǎo)胰島素樣生長因子-2（insulin-likegrowthfactor2，IGF-2）的表達(dá)，促進(jìn)突觸前末端的穩(wěn)定性，F(xiàn)GF22-IGF2通路介導(dǎo)的突觸穩(wěn)定性不足，極有可能參與抑郁發(fā)病機(jī)制[121]。

2.4 運(yùn)動與成纖維細(xì)胞生長因子家族

有關(guān)運(yùn)動改善神經(jīng)系統(tǒng)疾病的機(jī)制研究，涉及FGF的文獻(xiàn)相對匱乏。運(yùn)動可增加海馬FGF2水平，還可增加多個腦區(qū)的FGF2免疫活性[48]。自主運(yùn)動提高了雪旺氏細(xì)胞介導(dǎo)的FGF2基因治療對軸突再生的作用，而這可能是因?yàn)镕GF2提高了腰椎脊髓和被移植的雪旺氏細(xì)胞背根神經(jīng)節(jié)中再生相關(guān)蛋白（GAP-43和SYN）的水平，運(yùn)動后增加FGF2基因治療提高了有髓鞘軸突的再生[53]。抗阻運(yùn)動卻降低了老年小鼠骨骼肌FGF2的蛋白水平[67]。肌肉FGF2水平對衛(wèi)星細(xì)胞的分化極其關(guān)鍵，肌肉組織和腦組織間的對話可能為運(yùn)動介導(dǎo)FGF2發(fā)揮對腦的積極效應(yīng)提供通路，由此，F(xiàn)GF2可能成為運(yùn)動抗抑郁的重要媒介。本課題組研究發(fā)現(xiàn)，氟西汀或運(yùn)動干預(yù)可上調(diào)抑郁小鼠的FGF9水平，且FGF9/AKt/GSK3β/β-catenin通路紊亂可能是介導(dǎo)抑郁發(fā)生的一種信號機(jī)制[6]?；贔GF9與FGF2的拮抗作用，未來研究尚需對FGFs在運(yùn)動抗抑郁過程中的表現(xiàn)、作用及機(jī)制進(jìn)行深入探討。目前還未有實(shí)驗(yàn)對FGF22在運(yùn)動抗抑郁中的表現(xiàn)進(jìn)行例證，未來研究除圍繞FGF22本身展開外，還可以FGF22結(jié)合蛋白及其受體為切入點(diǎn)，以期明確FGF22與抑郁癥之間的關(guān)系，F(xiàn)GF22在介導(dǎo)運(yùn)動抗抑郁過程中的作用，從而為抑郁癥等精神障礙性疾病的治療提供新的治療靶點(diǎn)和思路。

3 生神經(jīng)細(xì)胞因子家族

生神經(jīng)細(xì)胞因子是一類可發(fā)揮神經(jīng)營養(yǎng)作用的細(xì)胞因子，目前國內(nèi)研究使用這一歸類名稱較少，但實(shí)際上其在國外研究中卻由來已久，該家族因子主要包括睫狀神經(jīng)營養(yǎng)因子（ciliary neurotrophic factor，CNTF）、IL-6、白血病抑制因子（leukemia inhibitory factor，LIF）[14]，這些因子是可以進(jìn)行免疫應(yīng)答的小分子蛋白質(zhì)，它們參與細(xì)胞的增殖和分化，調(diào)控突觸可塑性以及神經(jīng)系統(tǒng)的發(fā)育，并可能通過與5-HT系統(tǒng)、HPA軸及神經(jīng)可塑性間的作用影響抑郁病程，是精神障礙性疾病發(fā)病的一類重要影響因子[15]。

3.1 睫狀神經(jīng)營養(yǎng)因子（CNTF）

CNTF是一種從雞胚睫狀神經(jīng)元中分離出的多效能因子，廣泛分布于中樞和外周神經(jīng)系統(tǒng)，支持多種類型神經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞的存活，且對神經(jīng)元和少突膠質(zhì)細(xì)胞等都具有潛在的營養(yǎng)作用[96]。臨床研究發(fā)現(xiàn)，將封裝的CNTF膠囊植入亨廷頓患者右腦室2年后取出發(fā)現(xiàn)，有1/8的患者會被診斷為患有抑郁癥，提示，CNTF可能是與抑郁相關(guān)的神經(jīng)營養(yǎng)因子之一，可作為抑郁的外周標(biāo)志物[12]。CNTF缺失小鼠表現(xiàn)出焦慮行為增加，在習(xí)得性無助實(shí)驗(yàn)條件下，小鼠更容易出現(xiàn)抑郁行為，這些變化與海馬5-HT及其受體1A的表達(dá)相關(guān)，表明，內(nèi)源性CNTF對海馬功能結(jié)構(gòu)的維持起關(guān)鍵作用，因此，其對嚙齒類動物的焦慮、抑郁等情感行為存在重要影響[100]。外源性CNTF雖不能靈敏調(diào)控神經(jīng)遞質(zhì)的釋放，但卻能保護(hù)成熟終板免于活動誘發(fā)的突觸抑制[43]。CNTF對靶細(xì)胞發(fā)揮作用時涉及到一個由3個受體亞基組成的受體復(fù)合體，包括糖蛋白gp130、LIFRβ及CNTFRα，CNTF-CNTFR可能通過gp130/LIFRβ受體信號，激活Janus酪氨酸激酶2（Janus kinase 2，JAK2）/轉(zhuǎn)錄激活因子（signal transducer and activator of transcription，STAT）通路實(shí)現(xiàn)信號轉(zhuǎn)導(dǎo)[78]，Pasquin等[97]提出，CNTF也可能是通過該通路對神經(jīng)退行性疾病產(chǎn)生積極影響的。由此推論，CNTF通過CNTFR/gp130/LIFRβ/JAK/STAT通路介導(dǎo)的神經(jīng)遞質(zhì)釋放和突觸保護(hù)，成為CNTF介導(dǎo)抑郁的一種可能性，不過這還有待后續(xù)實(shí)驗(yàn)的進(jìn)一步論證。

運(yùn)動可增強(qiáng)大鼠下丘腦信號轉(zhuǎn)導(dǎo)和STAT3的磷酸化，降低細(xì)胞因子信號轉(zhuǎn)導(dǎo)抑制因子3（suppressor of cytokine signaling 3，SOCS3）的表達(dá)；JAK2/STAT3是瘦素（leptin）信號的主要通路，而CNTF下游信號與leptin相似，其中最突出的是STAT3[78,94]。在肥胖、糖尿病動物模型中，慢性注射CNTF可明顯改善糖脂代謝，調(diào)控新陳代謝。本課題組曾提出，抑郁癥與糖尿病共病的運(yùn)動干預(yù)機(jī)制可能是經(jīng)由瘦素受體（leptin receptor，LepRb）/炎性細(xì)胞因子（inflammatory cytokines，ICK）-SOCS3通路的瘦素抵抗[2]。CNTF可通過促進(jìn)GAP-43的表達(dá)改善神經(jīng)突生長、神經(jīng)元發(fā)育并抑制其凋亡，而這些作用是經(jīng)由JAK2/STAT3和PI3K/AKT實(shí)現(xiàn)的。SOCS3與LepRb相互影響且可抑制JAK2/STAT3信號通路，因此，CNTF的下游信號通路受到影響[80]。鑒于CNTF及其受體在肌肉中的豐富表達(dá)，結(jié)合抑郁的代謝假說，以及CNTF可防止神經(jīng)元發(fā)生退行性變化的強(qiáng)效，推測CNTFR/JAK2/STAT3可能介導(dǎo)了CNTF在運(yùn)動抗抑郁過程中的機(jī)制，而LepRb及SOCS3等都會影響這一過程。CNTF及其受體極有可能在運(yùn)動抗抑郁過程中發(fā)揮重要作用，未來對于CNTF在運(yùn)動抗抑郁過程中的進(jìn)一步深入研究，將為抑郁癥及其共病的研究和治療帶來新的希望。

3.2 白介素-6（IL-6）

IL-6主要由巨噬細(xì)胞和單核細(xì)胞刺激分泌，一般多認(rèn)為它是一種促炎性細(xì)胞因子，在免疫反應(yīng)的啟動維持中發(fā)揮重要作用，既往研究還發(fā)現(xiàn)，IL-6可增加神經(jīng)營養(yǎng)因子和神經(jīng)生長因子的分泌[68]，因此，包括IL-6在內(nèi)的許多免疫介質(zhì)還有另外一個身份，那就是作為生神經(jīng)細(xì)胞因子家族的一員，在腦發(fā)育及神經(jīng)退行性疾病中發(fā)揮作用[117]?？紤]到炎癥與多種神經(jīng)系統(tǒng)疾病有關(guān)，基于抑郁的“細(xì)胞因子假說”，抑郁可被看作是一種精神神經(jīng)系統(tǒng)免疫失調(diào)疾病。元分析顯示，抑郁癥患者血清IL-6濃度明顯升高，且血清IL-6濃度與抑郁程度呈正相關(guān)[142]?；颊哌M(jìn)行抗抑郁藥物治療后血清IL-6明顯下降，且多種抗抑郁藥物的作用機(jī)理與IL-6密切相關(guān)。IL-6活性增加與難治性抑郁有關(guān)，而血漿IL-6水平則可作為抑郁癥患者使用選擇性5-羥色胺再攝取抑制劑（selective serotonin reuptake inhibitor，SSRI）或選擇性去甲腎上腺素再攝取抑制劑（selective norepinephrine reuptake inhibitor，SNRI）類抗抑郁藥的指示物[141]。動物研究發(fā)現(xiàn)，IL-6通過激活ERK1/2介導(dǎo)了大鼠在強(qiáng)迫游泳中抑郁行為的改變[135]。IL-6與其受體結(jié)合后，激活下游的酪氨酸激酶2（tyrosine kinase 2，TYK2）和JAK1/2，導(dǎo)致STAT3磷酸化并調(diào)節(jié)5-HT轉(zhuǎn)運(yùn)和5-羥色胺轉(zhuǎn)運(yùn)體（serotonin transporter，SERT）基因轉(zhuǎn)錄[72]，進(jìn)而影響動物抑郁行為。與此相似，應(yīng)激大鼠下丘腦IL-6與IL-6R或gp130R結(jié)合后也激活了JAK/STAT3信號通路，并對HPA軸功能有重要影響，因此，可把HPA軸看作是IL-6與應(yīng)激之間的反應(yīng)中介之一[47]。綜上，IL-6可能通過相關(guān)受體經(jīng)由TYK2/JAK/STAT3激活SERT或ERK1/2通路，調(diào)節(jié)單胺類神經(jīng)遞質(zhì)水平或HPA軸功能，進(jìn)而介導(dǎo)抑郁的發(fā)生。

規(guī)律的運(yùn)動鍛煉具有一定的抗炎作用，運(yùn)動可改變IL-6水平、緩解炎癥反應(yīng)，從而改善抑郁的嚴(yán)重程度[106]。IL-6可激活小鼠肌肉和脂肪中AMP激活的蛋白激酶（AMP-activated protein kinase，AMPK）及其靶分子乙酰輔酶A羧化酶（Acetyl-CoA carboxylase，ACC），即增加其磷酸化程度，這些組織中AMPK活性的增加即為對運(yùn)動的適應(yīng)[64]。IL-6調(diào)控了皮下脂肪組織中急性運(yùn)動誘導(dǎo)的leptin表達(dá)下調(diào)，改變了IL-6Rα和過氧化物酶體增殖物激活受體γ（peroxisome proliferator-activated receptor γ，PPARγ）的mRNA水平[19]。本課題組曾提出，LepRb/ICK-SOCS3通路的leptin抵抗可能介導(dǎo)了抑郁癥與糖尿病共病的運(yùn)動干預(yù)機(jī)制[2]，且與IL-6同家族的IL-1β誘導(dǎo)的leptin水平增加可增強(qiáng)α1-腎上腺素受體（α1-adrenergic receptor，α1-AR）介導(dǎo)的抑郁行為[74]。由此可提出一種尚需證實(shí)的可能性，即運(yùn)動改變IL-6和leptin水平，與α1-AR或LepRb結(jié)合后經(jīng)由ICK-SOCS3介導(dǎo)對抑郁的調(diào)控。

3.3 白血病抑制因子（LIF）

LIF因可抑制小鼠M1白血病細(xì)胞的增殖而得名，此外，它也是一種涉及交感神經(jīng)、感覺和運(yùn)動神經(jīng)元存活、分化及再生的多效細(xì)胞因子，在神經(jīng)系統(tǒng)中表現(xiàn)活躍，因此，被歸為生神經(jīng)細(xì)胞因子家族的一員[102]。近年研究認(rèn)為其在中樞神經(jīng)系統(tǒng)損傷病變中發(fā)揮神經(jīng)保護(hù)和調(diào)節(jié)作用，可修復(fù)AD和抑郁等神經(jīng)精神疾病[108]。AD患者大腦LIF水平升高，分析認(rèn)為Aβ誘導(dǎo)的細(xì)胞分化和隨之產(chǎn)生的LIF可激活小膠質(zhì)細(xì)胞并增強(qiáng)AD的炎癥反應(yīng)，而LIF生成的增加卻又保護(hù)神經(jīng)元抵抗Aβ誘導(dǎo)的神經(jīng)毒性，因此，LIF是促炎因子還是抗炎因子至今難以定論[105, 116]。臨產(chǎn)期小鼠暴露于皮質(zhì)酮可引起子代抑郁行為，并伴隨下丘腦LIF表達(dá)上調(diào)[99]；LIF基因敲除小鼠在強(qiáng)迫游泳中抑郁行為減少[98]，提示，LIF可能成為抑郁病理的候選因子之一。新生大鼠皮下注射LIF后，在青春期階段表現(xiàn)出活動度下降，且在青春期或之后的聲音驚嚇反應(yīng)中表現(xiàn)為非正常脈沖抑制，卻在主動回避測試中表現(xiàn)出正常的學(xué)習(xí)能力，這可能是由于LIF誘導(dǎo)STAT3磷酸化，并增加新皮層膠質(zhì)原纖維酸性蛋白（glial fibrillary acidic protein，GFAP）的免疫反應(yīng)性[131]。TNF-α是與抑郁密切關(guān)聯(lián)的炎癥因子之一，TNF-α通過LIF自分泌激活STAT3并促進(jìn)星形膠質(zhì)細(xì)胞再生，TNF-α還可增加卵巢白陽性細(xì)胞和人體神經(jīng)祖細(xì)胞中LIF的表達(dá)，暗示了LIF與抑郁相關(guān)的可能性[75]。LIF通過LIFRβ/gp130受體，經(jīng)由STAT3、MAPK、PI3K通路分別調(diào)控小鼠胚胎干細(xì)胞的自我更新、細(xì)胞分化和細(xì)胞存活[50]，其中，gp130也是IL-6的受體之一。LIF/JAK/STAT3這一信號通路涉及誘導(dǎo)多能干細(xì)胞再生，雌激素相關(guān)受體β（estrogen-related receptor β，ESRRB）是該通路下游的重要調(diào)控因子[58]。LIF作為情緒和炎性應(yīng)激的反饋，其機(jī)制涉及HPA軸、免疫系統(tǒng)及因子間相互影響等，在子代發(fā)育過程中尤為敏感，這可能為子代抑郁研究提供針對性靶點(diǎn)，因此，LIF是抑郁研究中不容忽視的重要因子之一。

LIF是運(yùn)動誘導(dǎo)的肌肉因子，由體外肌細(xì)胞和骨骼肌產(chǎn)生釋放，是肌肉衛(wèi)星細(xì)胞分化和肌肉再生的關(guān)鍵調(diào)控因子。運(yùn)動時骨骼肌可能因細(xì)胞內(nèi)Ca2+濃度的震蕩而有效上調(diào)LIF的表達(dá)水平[21]，肌細(xì)胞Ca2+可能通過Ca2+/活化T細(xì)胞核因子（nuclear factor of active T cells，NFAT）/LIF信號激活LIF[20]。臨床研究發(fā)現(xiàn)，向心運(yùn)動后即刻骨骼肌LIF的mRNA增加且在恢復(fù)過程中逐漸下降，但其蛋白表達(dá)卻未發(fā)生一致改變[20]。力量和耐力訓(xùn)練后，運(yùn)動員血漿LIF濃度升高，且兩種運(yùn)動類型間LIF濃度也有明顯差異[62]。然而，動物研究卻發(fā)現(xiàn)，自主跑輪運(yùn)動后小鼠LIF的mRNA表達(dá)減少[20]。間歇運(yùn)動可上調(diào)心肌梗死模型大鼠肌肉LIF/LIFR的表達(dá)，并激活STAT3使其磷酸化[59]。運(yùn)動可調(diào)控LIF，這也被視為肌肉對運(yùn)動的一種適應(yīng)。鑒于同家族CNTF、IL-6的運(yùn)動抗抑郁機(jī)制均涉及STAT3，推測LIF亦有可能介入運(yùn)動抗抑郁機(jī)制。有關(guān)運(yùn)動對LIF影響的研究尚未形成定論，LIF在運(yùn)動抗抑郁機(jī)制方面的研究存在其必要性和特殊性，需進(jìn)一步補(bǔ)充完善。

4 膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子家族

膠質(zhì)細(xì)胞源性神經(jīng)生長因子家族成員包括膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子（glial cell line-derived neurotriphic factor，GDNF）、artemin（ARTN）、persephin（PSPN）和neurturin（NRTN），是對中樞和外周神經(jīng)元存活發(fā)揮潛在作用的蛋白質(zhì)，具有神經(jīng)保護(hù)和促進(jìn)神經(jīng)再生的作用，其可支持多巴胺能、感覺、運(yùn)動、海馬、基底前腦、腸、交感神經(jīng)和副交感神經(jīng)元等多種神經(jīng)元群體[113]。

4.1 膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子（GDNF）

GDNF是由膠質(zhì)細(xì)胞衍生出的神經(jīng)營養(yǎng)因子，對多巴胺神經(jīng)元、運(yùn)動神經(jīng)元、感覺神經(jīng)元有明顯的促再生作用，因其可預(yù)防神經(jīng)元退化，促進(jìn)神經(jīng)元存活的強(qiáng)效，目前在帕金森?。≒arkinson disease，PD）和AD等神經(jīng)退行性疾病的治療領(lǐng)域研究頗豐，其中一些已應(yīng)用至臨床階段。研究已發(fā)現(xiàn)，抑郁癥患者GDNF水平下降，治療后恢復(fù)正常，且GDNF水平與抑郁得分呈負(fù)相關(guān)。因此，GDNF可作為抑郁的外周標(biāo)志物，GDNF穩(wěn)態(tài)控制可能成為抑郁治療的新靶點(diǎn)[34]。動物研究發(fā)現(xiàn)，應(yīng)激所致抑郁通過機(jī)體反饋調(diào)節(jié)作用使大鼠海馬GDNF水平升高，而氟西汀對GDNF水平無明顯改變[8]。這可能由于GDNF在幾個神經(jīng)系統(tǒng)中都有所作用，也可能源自受損大腦的適應(yīng)性反應(yīng)，具體原因還需進(jìn)一步論證。應(yīng)激還可導(dǎo)致GDNF啟動子的DNA甲基化和MeCP2的募集，不同焦慮程度下小鼠MeCP2的募集分子也是不同的，MeCP2募集CREB可激活GDNF的轉(zhuǎn)錄，MeCP2募集HDAC2卻抑制GDNF的轉(zhuǎn)錄，這可能是其最終導(dǎo)致焦慮和抑郁行為的原因[85]。增加星型膠質(zhì)細(xì)胞中基質(zhì)金屬蛋白酶-9（matrix metalloproteinase-9，MMP-9）的活性會使GDNF表達(dá)增加，且MMP-3可激活MMP-9，MMP-9可調(diào)節(jié)細(xì)胞內(nèi)受體酪氨酸激酶（receptor tyrosine kinases，RTKs）和ERK信號，也對FGF2流出和FGFR激活起到至關(guān)重要作用，由此研究者提出，MMP-9/RTKs/ERK及MMP-9/FGF2/FGFR可能會使GDNF表達(dá)增加，并成為一種抗抑郁的治療路徑[9]。此外，GDNF也可能經(jīng)由GDNF家族受體α-1（GDNF family receptor α1，GFRα1）/神經(jīng)細(xì)胞粘附分子（neural cell adhesion molecule，NCAM）/MAPK或GFRα1/NCAM/AKT、GFRα1/ NCAM/RET（RTKs家族成員）等通路發(fā)揮神經(jīng)保護(hù)作用[83]。GDNF與認(rèn)知和情感都密切相關(guān)，其水平改變可作為抑郁誘發(fā)因素之一，也可理解為是對抑郁的適應(yīng)不良變化，受體、激酶等因素均可能影響其表達(dá)。

4.2 ARTN、PSPN和NRTN

ARTN是一種在中腦腹側(cè)多巴胺能神經(jīng)元結(jié)構(gòu)發(fā)育和可塑性中發(fā)揮重要作用的強(qiáng)有力神經(jīng)營養(yǎng)因子[144]。抑郁狀態(tài)下，患者外周血細(xì)胞中GDNF和ARTN的mRNA表達(dá)水平降低，但并未在BD患者中發(fā)現(xiàn)這些表達(dá)的改變，表明，GDNF和ARTN表達(dá)水平的變化與抑郁的病理機(jī)制有關(guān)，并可能是狀態(tài)依賴式的[90]。ARTN處理同樣會誘發(fā)小鼠產(chǎn)生劑量依賴式的抗抑郁表現(xiàn)[33]。且ARTN與GFRα3或RET結(jié)合后可能誘導(dǎo)大鼠受損軸突的長距離再生，因此，ARTN內(nèi)在通路對中樞神經(jīng)系統(tǒng)軸突再生治療是有益的[133]。PSPN和NRTN與GDNF一樣，對多巴胺能神經(jīng)元具有顯著的營養(yǎng)、支持和損傷修復(fù)作用。PSPN是中樞神經(jīng)系統(tǒng)興奮性的有效調(diào)節(jié)劑，具有顯著的神經(jīng)保護(hù)活性，其對谷氨酸鈣穩(wěn)態(tài)受損的腦疾病AD與PD等均有治療效果[123]。研究發(fā)現(xiàn)，PSPN能預(yù)防體內(nèi)多巴胺能神經(jīng)元的退行性病變，通過保護(hù)多巴胺能神經(jīng)元，對6-羥基多巴胺（6-hydroxydopanine，6-OHDA）誘導(dǎo)的PD模型大鼠發(fā)揮神經(jīng)保護(hù)作用[139]。NRTN在促進(jìn)多巴胺能神經(jīng)元存活、部分外周神經(jīng)元以及膠質(zhì)細(xì)胞的分化方面發(fā)揮著重要的生理作用[3]，其在多巴胺能神經(jīng)元中過度表達(dá)，可誘導(dǎo)慢性6-OHDA損傷大鼠黑質(zhì)紋狀體多巴胺能系統(tǒng)突觸前和突觸后的結(jié)構(gòu)改變，促進(jìn)神經(jīng)突生長[107]。目前，該家族因子主要集中于PD疾病治療方面的研究，關(guān)于抑郁癥的研究較少，但鑒于該家族因子均參與促進(jìn)成熟海馬神經(jīng)元的皮質(zhì)發(fā)育、功能活動及維持，提示，除GDNF外，該家族因子ARTN、PSPN和NRTN也可能與抑郁病理及治療有關(guān)[103]。

4.3 運(yùn)動與膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子家族

研究發(fā)現(xiàn)，運(yùn)動可影響GDNF水平，低強(qiáng)度有氧跑臺運(yùn)動可明顯升高血漿、神經(jīng)及肌肉的GDNF水平，并誘導(dǎo)神經(jīng)再生[93]。耐力運(yùn)動可增加比目魚肌和趾長伸肌GDNF表達(dá)，其表達(dá)與神經(jīng)肌肉接頭的形態(tài)學(xué)變化是活動依賴性的，且運(yùn)動強(qiáng)度的變化可能會導(dǎo)致其變化程度的不同[52]。生長期大鼠進(jìn)行非自主運(yùn)動，其脊髓GDNF蛋白含量出現(xiàn)6倍增加，游泳運(yùn)動使其出現(xiàn)3倍增加，自主跑步運(yùn)動后呈雙倍增加[84]。運(yùn)動可使5-HT的表達(dá)增加，而5-HT可由5-HTR介導(dǎo)的FGFR2反式激活后經(jīng)MEK（MAPK激酶）/ERK/CREB信號調(diào)控GDNF表達(dá)[127]。身體活動可刺激神經(jīng)營養(yǎng)因子的產(chǎn)生和釋放，通過減弱氧化應(yīng)激和抑制免疫過程，從而阻擋與多巴胺神經(jīng)元有關(guān)的神經(jīng)退行性疾病，適度身體活動更好的支持了神經(jīng)退行性疾病的藥理學(xué)治療[92]。雖未見GDNF介導(dǎo)運(yùn)動抗抑郁的文獻(xiàn)，但鑒于GDNF與多巴胺能神經(jīng)元和運(yùn)動神經(jīng)元的關(guān)聯(lián)，可推斷GDNF參與了運(yùn)動對抑郁的調(diào)控。運(yùn)動訓(xùn)練可阻止神經(jīng)病理性疼痛的發(fā)展，同時使GDNF和ARTN水平正?；痆32]。交感神經(jīng)元和多巴胺神經(jīng)元均與運(yùn)動密切相關(guān)，ARTN是感覺和交感神經(jīng)元的重要存活因子，且ARTN也可能通過激活GFRa1/RET的相關(guān)通路支持多巴胺能中腦神經(jīng)元[13]。PGC-1α的骨骼肌轉(zhuǎn)導(dǎo)可增加NRTN的分泌以及神經(jīng)肌肉接頭的形成和大小，由此認(rèn)為NRTN可能是肌肉到運(yùn)動神經(jīng)元逆向信號的中介物[86]。GDNF家族神經(jīng)營養(yǎng)因子在運(yùn)動方面的研究不多，但據(jù)目前的研究結(jié)果來看，部分家族成員已被發(fā)現(xiàn)與抑郁相關(guān)，且對運(yùn)動神經(jīng)元和多巴胺能神經(jīng)元受損的神經(jīng)退行性疾病表現(xiàn)出較強(qiáng)的調(diào)控作用，因此，考慮該家族因子同樣有可能參與了運(yùn)動對抑郁的調(diào)控，仍需進(jìn)一步研究證實(shí)。

5 其他神經(jīng)營養(yǎng)因子

5.1 血管內(nèi)皮生長因子（VEGF）

VEGF可促進(jìn)海馬神經(jīng)發(fā)生及內(nèi)外信號轉(zhuǎn)導(dǎo)，發(fā)揮神經(jīng)保護(hù)作用并影響突觸傳遞，而抑郁發(fā)病與海馬神經(jīng)發(fā)生相關(guān)。基因多態(tài)性臨床研究發(fā)現(xiàn)，VEGF rs2010963可增加重度抑郁發(fā)病風(fēng)險[55]，VEGF rs4416670也與抑郁發(fā)病風(fēng)險的增加相關(guān)[136]。重度抑郁和雙相情感障礙躁狂發(fā)作期患者的VEGF水平升高，分析認(rèn)為，VEGF的這種改變可能與它在情緒障礙中的神經(jīng)保護(hù)作用有關(guān)[76]。精神抑郁癥患者miR-126-3p、miR-106a-5p和VEGFA水平升高，電休克治療后全血miR表達(dá)恢復(fù)正常，其共同靶點(diǎn)VEGFA明顯降低[71]。抑郁或焦慮患者氯胺酮治療后，其血清VEGF水平降低[40]。動物研究也發(fā)現(xiàn)，抗抑郁藥可降低應(yīng)激小鼠海馬VEGF水平[51]。VEGF可降低大腦NE和5-HT水平，VEGF依賴的抗抑郁反應(yīng)涉及單胺能系統(tǒng)，尤其是NE系統(tǒng)[129]。VEGF在小鼠海馬神經(jīng)元中靠NMDA型谷氨酸受體介導(dǎo)突觸后反應(yīng)增加，并誘發(fā)NR2B和α-氨基-3-羥基-5-甲基-4-異惡唑丙酸（α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, AMPA）受體的快速重新分布，隨后激活鈣調(diào)素激活激酶II（calcium/ calmodulin-dependent protein kinase II，CaMKII）和PKC。此外，神經(jīng)元沉默VEGFR2的表達(dá)會損害海馬突觸可塑性和情感記憶[30]。由此推測，VEGF作為谷氨酸受體突觸功能的關(guān)鍵調(diào)控者有望成為新的抑郁治療靶點(diǎn)。

運(yùn)動可下調(diào)VEGF水平，提示，運(yùn)動對抑郁的改善可能由VEGF介導(dǎo)。受試者運(yùn)動后前額葉和大腦顳葉BDNF和VEGF水平間呈負(fù)相關(guān)，這也提示，血液中的VEGF水平極有可能成為像BDNF一樣的抑郁外周標(biāo)志物[77]，且有氧抗阻聯(lián)合運(yùn)動對血液VEGF水平的降低作用比單一運(yùn)動形式更加明顯[41]。急性運(yùn)動可增加VEGF受體fms樣酪氨酸激酶-1（fms-like tyrosine kinase-1，F(xiàn)lt-1）及其mRNA表達(dá)，F(xiàn)lt-1隨后可能與PI3K結(jié)合刺激MAPK和纖溶酶原激活劑（plasminogen activator，PA），且NO在運(yùn)動對Flt-1基因的調(diào)控中扮演了重要角色[46]。運(yùn)動可治療應(yīng)激小鼠抑郁行為，這可能是VEGF經(jīng)其另一受體胎肝激酶-1（fetal liver kinase-1，F(xiàn)IK-1）介導(dǎo)的[70]。機(jī)械牽拉使VEGF的mRNA和蛋白表達(dá)增加可能是突觸神經(jīng)元對牽拉的一種適應(yīng)，由NGF/CNTF/TrkA通路經(jīng)低氧誘導(dǎo)因子-1α（hypoxia-inducible factor-1α，HIF-1α）的表達(dá)來進(jìn)行調(diào)控[111]。VEGF是運(yùn)動抗抑郁的重要因子，相關(guān)信號FIK-1、Flt-1/PI3K、NGF/CNTF/TrkA/HIF-1α等均可能參與到了VEGF的運(yùn)動抗抑郁調(diào)控機(jī)制中。

5.2 胰島素樣生長因子-1（IGF-1）

IGF-1是一種分子量較小的多肽氨基酸，具有神經(jīng)營養(yǎng)、神經(jīng)發(fā)生、神經(jīng)保護(hù)等功效，對中樞神經(jīng)系統(tǒng)的發(fā)育成熟及細(xì)胞的生長、存活和分化具有神經(jīng)內(nèi)分泌調(diào)節(jié)作用，因此，IGF-1可能參與了諸如抑郁等情感性障礙疾病的病理過程[118]。抑郁癥患者血清IGF-1水平降低，藥物治療后血清IGF-1上調(diào)，且IGF-1水平變化與皮質(zhì)酮變化顯著相關(guān)[73]。但也有研究發(fā)現(xiàn)，抑郁焦慮患者血漿IGF-1水平更高，抗抑郁藥物使用者更低，這可能是一種受損神經(jīng)發(fā)生的代償機(jī)制[18]。對老年抑郁癥患者的研究發(fā)現(xiàn)，低濃度IGF-1可增加女性患者重度抑郁的發(fā)病，而適中濃度的IGF-1可減少男性患者輕度抑郁的發(fā)病[130]。IGF-1可減少炎性標(biāo)志物的表達(dá)，促炎性細(xì)胞因子和腎上腺素是外周抑制IGF-1的主要因素[118]。IGF-1與受體IGF-1R結(jié)合后經(jīng)MEK1/2/ERK1/2通路或者通過與胰島素受體底物-1（insulin receptor substrate-1，IRS-1）結(jié)合后經(jīng)PI3K/AKT通路影響細(xì)胞存活，另一方面，通過雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）影響蛋白質(zhì)合成，或通過抑制GSK3β經(jīng)β-catenin調(diào)節(jié)細(xì)胞因子表達(dá)，而PI3K/AKT/GSK3/ mTOR通路與精神疾病密切相關(guān)，因此，Szczsny等提出腦內(nèi)IGF-1信號可調(diào)控精神疾病[69,118]。IGF-1可增強(qiáng)BDNF的合成和表達(dá)，二者均能提高大腦神經(jīng)存活并增強(qiáng)突觸可塑性，因此，探究IGF-1與抑郁的關(guān)系十分必要[124]。

運(yùn)動對抑郁有改善作用，IGF-1可能是調(diào)控因素之一。抗阻運(yùn)動后老年受試者焦慮抑郁風(fēng)險降低，并伴隨血清IGF-1水平升高[23]。應(yīng)激小鼠經(jīng)IGF-1治療后抑郁行為減少，外周抗IGF-1注射可抑制運(yùn)動的抗抑郁效果，說明，IGF-1介導(dǎo)了運(yùn)動的抗抑郁機(jī)制[35]。運(yùn)動對腦功能的影響包括改善認(rèn)知和減輕焦慮，主要取決于IGF-1的循環(huán)水平，且與海馬神經(jīng)發(fā)生的增加有關(guān)[125]。中樞神經(jīng)系統(tǒng)攝取外周的IGF-1對于運(yùn)動和抗抑郁藥誘導(dǎo)的海馬BDNF表達(dá)升高及神經(jīng)元存活和可塑性是至關(guān)重要的，且外周抗IGF-1處理可逆轉(zhuǎn)運(yùn)動及抗抑郁藥誘導(dǎo)的BDNF mRNA和蛋白表達(dá)的增加，這意味著運(yùn)動可能依靠外周IGF-1參與抑郁調(diào)節(jié)[25]。也有研究并未發(fā)現(xiàn)任何因運(yùn)動而導(dǎo)致的VEGF、IGF/IGF結(jié)合蛋白或BDNF明顯增加，這可能是由于運(yùn)動對這些因子的影響是瞬時的[82]。IGF-1參與了運(yùn)動誘導(dǎo)的抗抑郁活動，但具體機(jī)制還有待進(jìn)一步明晰，其與BDNF、VEGF等神經(jīng)營養(yǎng)因子之間的相互作用和影響，也可成為未來研究的關(guān)注點(diǎn)和突破點(diǎn)。

6 小結(jié)與展望

抑郁的神經(jīng)營養(yǎng)假說是抑郁病理機(jī)制中的重要假說之一，抑郁癥患者表現(xiàn)出多種NTFs的表達(dá)上調(diào)或下調(diào)，環(huán)境變化（如應(yīng)激等）、藥物使用、表觀遺傳調(diào)控（如miRs等）均可影響NTFs表達(dá)，這些變化在諸如海馬、下丘腦等情感相關(guān)腦區(qū)更為明顯，而運(yùn)動則能逆轉(zhuǎn)或緩解這種異常表達(dá)，進(jìn)而改善抑郁行為。本文綜述了幾種與抑郁密切相關(guān)的NTFs及其介導(dǎo)運(yùn)動抗抑郁的可能機(jī)制（圖1），運(yùn)動可調(diào)節(jié)NTFs的表達(dá)水平，使其表達(dá)上調(diào)或下調(diào)。遺憾的是，運(yùn)動對某些因子的調(diào)節(jié)作用尚存在爭議或仍不明確，有待后續(xù)研究進(jìn)一步補(bǔ)充完善。NTFs最終作用于神經(jīng)元并發(fā)生一系列的信號轉(zhuǎn)導(dǎo)，使得大腦神經(jīng)可塑性增強(qiáng)、神經(jīng)發(fā)生增加、細(xì)胞存活提高、HPA軸正常激活、單胺類神經(jīng)遞質(zhì)平衡、中樞炎癥緩解，從而實(shí)現(xiàn)與抑郁的對話機(jī)制。但仍有一些問題需進(jìn)一步明確或深入探究：1）NTFs表達(dá)隨抑郁嚴(yán)重程度的不同而不同，那么，如何量化這種相關(guān)關(guān)系；2）運(yùn)動抗抑郁過程中，NTFs是重要的介導(dǎo)分子，那么，不同NTFs間是否存在交互影響，如果有，具體作用機(jī)制又是什么；3）運(yùn)動對NTFs表達(dá)的改變是否存在“運(yùn)動處方特異性”，即不同的運(yùn)動方式、強(qiáng)度、時間等是否對NTFs有不同影響，從而導(dǎo)致對抑郁的改善程度也有所不同；4）某些NTFs在外周富集，那么，是否可篩選出這些外周營養(yǎng)因子作為抑郁癥液體活檢、運(yùn)動干預(yù)的生物標(biāo)記。這將會提高抑郁癥的診斷準(zhǔn)確率，并為研發(fā)抗抑郁藥物提供新靶點(diǎn)，為制定個性化抑郁癥運(yùn)動干預(yù)策略提供參考依據(jù)和方法。隨著研究的深入和拓展，NTFs在抑郁及運(yùn)動抗抑郁版圖中的機(jī)制網(wǎng)絡(luò)將會逐漸得以完善，這將為抑郁癥的研究與治療提供更多可能性。

圖1 神經(jīng)營養(yǎng)因子介導(dǎo)運(yùn)動抗抑郁的可能機(jī)制

Figure1. The Roles of Neurotrophic Factors in the Antidepressant Effects of Exercise

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Mediating Mechanism of Neurotrophic Factors in Antidepressant Effects of Exercise

LIU Wen-bin1,2, LIU Wei-na1,2, QI Zheng-tang1,2

1.Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China;2.School of Physical Education and Health Care, East China Normal University, Shanghai 200241, China.

Neurotrophic factors play a role in the development, survival and apoptosis of neurons, because of its important role in the neurodevelopment and neuroplasticity, it has long been paid much attention in the field of neuroscience. The neurotrophic hypothesis of depression believed that depression can lead to changes in the expression level of neurotrophic factors, the serum level and brain region expression of various neurotrophic factors in patients with depression are significantly different from the healthy individuals, this suggests that neurotrophic factors may become a new marker of depression. Exercise can regulate neuroplasticity, neurogenesis, cell survival, hypothalamic-pituitary-adrenal axis activity, monoamine neurotransmitters, central inflammation and then play antidepressant effects by changing the expression level of many neurotrophic factors, including nerve growth factor gene family, fibroblast growth factor family, neuropoietic cytokine family, glial cell line-derived neurotrophic factor family and other neurotrophic factors such as vascular endothelial growth factor and insulin like growth factor-1. This paper reviews mediating mechanism of neurotrophic factors in antidepressant effects of exercise, we hope to find “peripheral neurotrophic factors” as depression biomarkers used for biopsy and exercise intervention, and the findings are supposed to suggest more possibilities for research and treatment of depression .

G804.5

A

1000-677X(2018)10-0054-13

10.16469/j.css.201810007

2018-07-28；

2018-09-27

國家自然科學(xué)基金資助項(xiàng)目(31871208);上海市自然科學(xué)基金資助項(xiàng)目(18ZR1412000);中央高?；究蒲袠I(yè)務(wù)費(fèi)專項(xiàng)資金資助項(xiàng)目(2017ECNU-HWFW026); “青少年健康評價與運(yùn)動干預(yù)”教育部重點(diǎn)實(shí)驗(yàn)室建設(shè)項(xiàng)目(40500-541235-14203/004)。

劉文彬,女,在讀碩士研究生,主要研究方向?yàn)橐钟舭Y的運(yùn)動干預(yù),Email:liuwenbin1993@126.com。

劉微娜,女,副教授,博士,博士研究生導(dǎo)師,主要研究方向?yàn)橐钟舭Y的運(yùn)動干預(yù),E-mail:weina1978@126.com。