基于內(nèi)源性大麻素系統(tǒng)的抑郁癥發(fā)病機(jī)制及其在中藥研究中的應(yīng)用

陳佳俊，秦雪梅，杜冠華，周玉枝*

基于內(nèi)源性大麻素系統(tǒng)的抑郁癥發(fā)病機(jī)制及其在中藥研究中的應(yīng)用

陳佳俊1, 2, 3，秦雪梅1, 2, 3，杜冠華1, 4，周玉枝1, 2, 3*

1. 山西大學(xué) 中醫(yī)藥現(xiàn)代研究中心，山西 太原 030006 2. 山西大學(xué) 化學(xué)生物學(xué)與分子工程教育部重點(diǎn)實(shí)驗(yàn)室，山西 太原 030006 3. 地產(chǎn)中藥功效物質(zhì)研究與利用山西省重點(diǎn)實(shí)驗(yàn)室，山西 太原 030006 4. 中國醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)學(xué)院藥物研究所，北京 100050

抑郁癥是一種難以調(diào)控的疾病，目前缺乏高效、穩(wěn)定且安全的抗抑郁藥，尋找抑郁癥發(fā)病新機(jī)制對(duì)抗抑郁藥物的研發(fā)具有重要意義。近年來，研究發(fā)現(xiàn)抑郁癥與內(nèi)源性大麻素系統(tǒng)（endocannabinoid system，ECS）的紊亂密切相關(guān)，然而涉及的機(jī)制較為復(fù)雜，亟待整理。當(dāng)下，通過ECS的調(diào)控來治療抑郁癥是一種新途徑，而中藥在該途徑上存在天然優(yōu)勢，從中開發(fā)抗抑郁新藥具有廣泛的研究前景。鑒于此，對(duì)ECS與抑郁癥的關(guān)系及中藥介導(dǎo)ECS發(fā)揮抗抑郁作用的潛力進(jìn)行了分析，以期為抑郁癥發(fā)病機(jī)制的研究提供參考，為抗抑郁藥物的研發(fā)提供新策略。

內(nèi)源性大麻素系統(tǒng)；抑郁癥；發(fā)病機(jī)制；植物大麻素；大麻素受體

抑郁癥是一種難以治療的精神類疾病，嚴(yán)重影響社會(huì)生活，不幸的是，目前中國的抑郁癥患者僅約0.5%得到充分治療[1]。臨床上常用的抗抑郁藥起效慢，存在不良反應(yīng)，藥效也不盡人意，開發(fā)高效、穩(wěn)定且安全的抗抑郁藥物迫在眉睫[2]。探明抑郁癥發(fā)病機(jī)制，并使用安全穩(wěn)定的天然藥物對(duì)癥下藥，有望成為高效治療抑郁癥的新途徑。在對(duì)抑郁癥發(fā)病機(jī)制的研究中，諸多假說支持了以往抗抑郁藥物的研發(fā)，如單胺類神經(jīng)遞質(zhì)缺乏假說、炎癥假說、腸道菌群改變假說、神經(jīng)營養(yǎng)因子障礙假說[3]，但對(duì)抑郁癥發(fā)病過程的闡釋及治療對(duì)策的供給仍不夠全面。近年來，靶向內(nèi)源性大麻素系統(tǒng)（endocannabinoid system，ECS）治療抑郁癥的思路越來越受到關(guān)注，增強(qiáng)ECS信號(hào)有潛力成為抑郁癥治療的新選擇[4]。眾所周知，中醫(yī)藥因其在抑郁癥治療中的獨(dú)特療效而深受重視，以往研究發(fā)現(xiàn)，一些中藥及其活性成分能夠介導(dǎo)ECS調(diào)控抑郁癥，并且逐漸有證據(jù)表明從中藥中尋找作用于ECS的抗抑郁活性物質(zhì)具有廣泛的研究前景。

1 ECS

ECS是人腦中分布最為廣泛的神經(jīng)遞質(zhì)系統(tǒng)之一，主要由大麻素受體、內(nèi)源性大麻素及其合成和降解相關(guān)的酶組成[5]。大麻素受體研究最多的是大麻素1型/2型受體（type 1/2 cannabinoid receptor，CB1R/CB2R），主要位于γ-氨基丁酸（γ-aminobutyric acid，GABA）能和谷氨酸（glutamic acid，Glu）能神經(jīng)元突觸末梢，負(fù)責(zé)調(diào)控神經(jīng)遞質(zhì)的釋放[6-7]。除了調(diào)控神經(jīng)遞質(zhì)，CB2R還可介導(dǎo)小膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞和神經(jīng)元發(fā)揮免疫調(diào)節(jié)作用[8]。相對(duì)于經(jīng)典的大麻素受體，一些非大麻素受體也參與了ECS的生物學(xué)過程，如瞬時(shí)受體電位陽離子通道亞家族V成員1（transient receptor potential vanilloid 1，TRPV1）和過氧化物酶體增殖物激活受體（peroxisome proliferator-activated receptors，PPARs）[9]。另外，G蛋白偶聯(lián)受體（G protein-coupled receptor，GPR）18、GPR55、GPR119也能參與ECS的一些反應(yīng)[10]，其中，GPR55雖與經(jīng)典的CB1R和CB2R結(jié)構(gòu)上有所區(qū)別，但部分大麻素也能與GPR55結(jié)合并發(fā)揮作用，GPR55因此被認(rèn)為是一種非典型的大麻素受體[11]。與大麻素受體結(jié)合的內(nèi)源性大麻素主要有2種，分別是-花生四烯酰乙醇胺（-arachidonoyl- ethanolamide，AEA）和2-花生四烯酸甘油（2- arachidonoyl glycerol，2-AG），均從突觸后末梢合成并釋放，傳遞逆行信號(hào)并作用于突觸前末梢的CB1R和CB2R[12]。此外，還有2種類內(nèi)源性大麻素：-棕櫚酰乙醇胺（-palmitoylethanolamide，PEA）和油酰乙醇酰胺（oleoylethanolamide，OEA），PEA、OEA與AEA一樣，均在-?；字Ｒ掖及妨字窪（-acylphosphatidylethanolamine phospholipase D，NAPE-PLD）的生物作用下合成，作用于突觸膜受體或與內(nèi)源性大麻素膜轉(zhuǎn)運(yùn)體（endocannabinoid membrane transporters，EMT）在突觸末梢結(jié)合，最終由脂肪酸酰胺水解酶（fatty acid amide hydrolase，F(xiàn)AAH）代謝為乙醇胺和花生四烯酸（arachidonic acid，AA）[12]。ECS中的大麻素合成酶是NAPE-PLD和二?；视椭久?α/β（diacylglycerol lipase-α/β，DAGL-α/β），NAPE-PLD主要將-酰基磷脂酰乙醇胺催化合成AEA，DAGL-α/β則主要將二?；视痛呋铣?-AG，這2種大麻素合成酶均對(duì)鈣水平敏感[13]。ECS中的大麻素代謝酶主要是FAAH和單酰甘油脂肪酶（monoacylglycerol lipase，MAGL），分別負(fù)責(zé)分解AEA和2-AG[13]，除了這2種代謝酶，環(huán)氧合酶-2（cyclooxygenase-2，COX-2）也能代謝AEA和2-AG，并生成前列腺素衍生物[14]。

2 ECS與抑郁癥

近年來，大量研究表明ECS中內(nèi)源性大麻素及其受體介導(dǎo)的生物學(xué)過程參與抑郁癥的發(fā)病機(jī)制，通過增強(qiáng)ECS信號(hào)可有效改善與抑郁癥相關(guān)的功能障礙。

2.1 內(nèi)源性大麻素與抑郁癥

來自臨床和臨床前的研究表明，內(nèi)源性大麻素水平的變化與抑郁癥的調(diào)控密切相關(guān)。有研究在抑郁癥患者的血清和大腦中發(fā)現(xiàn)AEA和2-AG濃度均有所降低[15-16]，而在抑郁癥動(dòng)物模型的大腦中也發(fā)現(xiàn)了類似的情況[17-18]，有趣的是，不同的抗抑郁治療途徑似乎都能顯著提高AEA或2-AG水平[18-20]，提示內(nèi)源性大麻素可能具有抗抑郁活性，上調(diào)大麻素水平則具有一定的抗抑郁作用。經(jīng)研究得知，AEA和2-AG介導(dǎo)的抗抑郁作用可能與腦源性神經(jīng)營養(yǎng)因子（brain-derived neurotrophic factor，BDNF）水平的提高[16]、皮質(zhì)酮水平的降低[21]、雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信號(hào)的傳遞[22]、神經(jīng)發(fā)生和突觸可塑性的增強(qiáng)[23]有關(guān)。此外，有研究發(fā)現(xiàn)，與AEA結(jié)構(gòu)類似的PEA可以增強(qiáng)西酞普蘭的抗抑郁藥效[24]，提示PEA也有潛在的抗抑郁活性。隨后，有研究考察了PEA的抗抑郁作用[25]，發(fā)現(xiàn)PEA具有神經(jīng)保護(hù)功能，外源增補(bǔ)PEA后顯著改善了慢性不可預(yù)測溫和應(yīng)激（chronic unpredictable mild stress，CUMS）大鼠的抑郁樣行為，并且降低了抑郁模型大鼠血清中異常升高的促腎上腺皮質(zhì)激素和皮質(zhì)酮，逆轉(zhuǎn)了氧化應(yīng)激反應(yīng)，同時(shí)還增加了神經(jīng)營養(yǎng)因子的濃度，而PPAR-α被認(rèn)為是PEA發(fā)揮這些作用的潛在靶點(diǎn)。相隔不久，又有研究表明PEA可介導(dǎo)PPAR-α通過四氫孕酮的生物合成改善抑郁癥[26]，提示PPAR-α介導(dǎo)的相關(guān)生物學(xué)途徑與PEA的抗抑郁作用有緊密聯(lián)系。除了2-AG、AEA和PEA，OEA也表現(xiàn)出了一定的抗抑郁活性[27]，據(jù)報(bào)道，OEA的抗抑郁作用與激素水平的調(diào)節(jié)和神經(jīng)炎癥的抑制相關(guān)[28]，具體的調(diào)控機(jī)制仍需深入研究。值得注意的是，體育運(yùn)動(dòng)對(duì)抑郁癥的緩解有很大幫助，有報(bào)道發(fā)現(xiàn)體育運(yùn)動(dòng)介導(dǎo)的抗抑郁作用與抑郁癥患者體內(nèi)AEA、OEA和PEA水平的提高有關(guān)[29]，再次表明內(nèi)源性大麻素信號(hào)的增強(qiáng)有助于減輕抑郁癥狀。除了以上生物學(xué)途徑，內(nèi)源性大麻素還可能在維持血腦屏障的完整性和功能方面對(duì)抑郁癥的調(diào)節(jié)發(fā)揮積極作用[30]，有待進(jìn)一步研究。

2.2 內(nèi)源性大麻素受體與抑郁癥

CB1R和CB2R激活后介導(dǎo)的抗抑郁作用已被報(bào)道[31]，其中，CB1R主要參與神經(jīng)調(diào)節(jié)，而CB2R則側(cè)重于免疫調(diào)節(jié)。經(jīng)研究發(fā)現(xiàn)，CB1R激活后介導(dǎo)的抗抑郁作用主要與5-羥色胺（5-hydroxytryptamine，5-HT）能和去甲腎上腺素（noradrenaline，NA）能的調(diào)控[32]、神經(jīng)發(fā)生和突觸可塑性的增強(qiáng)[33]、基底外側(cè)杏仁核-伏隔核神經(jīng)環(huán)路突觸傳遞的抑制[34]及細(xì)胞外調(diào)節(jié)蛋白激酶1/2（extracellular regulated protein kinase 1/2，ERK1/2）的激活[35]有關(guān)。相比于CB1R，CB2R激活后介導(dǎo)的抗抑郁作用似乎與神經(jīng)炎癥的緩解更為相關(guān)[36]，CB2R激活后能夠阻止應(yīng)激誘導(dǎo)的腫瘤壞死因子-α（tumor necrosis factor，TNF-α）、CC趨化因子配體2（CC chemokine ligand 2，CCL2）、核因子-κB（nuclear factor-κB，NF-κB）、一氧化氮合成酶-2（nitric oxide synthetase-2，NOS-2）和COX-2的異常增加，此外，CB2R介導(dǎo)的抗抑郁作用與單胺能系統(tǒng)的調(diào)控[37]、BDNF水平的提高[38]也有一定聯(lián)系。近期研究表明，CB1R的激活和CB2R的上調(diào)均能減少大腦中的氧化應(yīng)激水平，從而減輕組織損傷和神經(jīng)炎癥[39]，進(jìn)一步提示CB1R和CB2R的激活有助于改善抑郁癥導(dǎo)致的神經(jīng)損傷。有趣的是，過去曾發(fā)現(xiàn)CB2R的激活能夠促進(jìn)神經(jīng)前體細(xì)胞的增殖[40]、增強(qiáng)海馬體CA2和CA3區(qū)錐體細(xì)胞的可塑性[41]，而今又發(fā)現(xiàn)CB2R能介導(dǎo)小膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞和神經(jīng)元參與免疫調(diào)節(jié)[8]，提示CB2R激活后介導(dǎo)的抗抑郁作用可能與神經(jīng)細(xì)胞的調(diào)節(jié)有關(guān)，需進(jìn)一步探明。GPR55作為ECS中非典型的大麻素受體，在抑郁癥的治療中具有潛在前景[42]。最近研究表明，海馬中GPR55蛋白表達(dá)的下降可能會(huì)介導(dǎo)抑郁樣行為的發(fā)生，相反，GPR55的激活或上調(diào)則具有潛在的抗抑郁作用，而這種抗抑郁作用被認(rèn)為與GPR55受體激活后產(chǎn)生的抗炎和神經(jīng)保護(hù)作用有關(guān)[43]。

2.3 ECS與抑郁癥相關(guān)功能障礙

大麻二酚（cannabidiol，CBD）是藥用植物大麻中的非成癮性大麻素，自從ECS及其在神經(jīng)精神疾病的作用被首次認(rèn)識(shí)以來，CBD一直是許多臨床和臨床前研究的主題[44]，CBD是ECS的基本組成部分，能夠通過多種生物學(xué)途徑改善抑郁癥[4]，提示ECS對(duì)抑郁癥相關(guān)功能障礙的調(diào)節(jié)至關(guān)重要。首先，CBD可以調(diào)節(jié)單胺類神經(jīng)遞質(zhì)，通過增加5-HT和NA水平發(fā)揮抗抑郁作用[45]；其次，CBD能平衡下丘腦-垂體-腎上腺（hypothalamic-pituitary- adrenal，HPA）軸相關(guān)功能[46]，改善激素水平，如調(diào)節(jié)皮質(zhì)酮[47]；另一方面，CBD還能通過激活BDNF-酪氨酸激酶受體B（tyrosine receptor kinase B，TrkB）通路來改善大腦突觸可塑性[48]。不僅如此，ECS在抑郁癥相關(guān)的代謝調(diào)控方面也有參與。曾有研究報(bào)道，促炎細(xì)胞因子水平的升高可能會(huì)過度激活犬尿氨酸途徑（kynurenine pathway，KP），KP負(fù)責(zé)代謝色氨酸，色氨酸是5-HT合成的前體，而KP的過度激活會(huì)導(dǎo)致色氨酸耗竭和5-HT水平降低，從而引發(fā)抑郁癥，該過程被認(rèn)為與ECS的調(diào)控有關(guān)[49]。不久前有研究佐證了這一點(diǎn)，發(fā)現(xiàn)CBD的抗抑郁作用與抑制KP和NF-κB的激活及白細(xì)胞介素（interleukin，IL）-6的釋放相關(guān)[50]，但ECS參與調(diào)控的具體機(jī)制尚待細(xì)究。此外，Toll樣受體（Toll-like receptor，TLR）3/4激活后介導(dǎo)的神經(jīng)炎癥與抑郁癥發(fā)病機(jī)制也存在聯(lián)系，而TLR相關(guān)炎癥同樣受ECS的調(diào)控，TLR相關(guān)神經(jīng)炎癥的ECS調(diào)節(jié)可能會(huì)成為抑郁癥治療的新方向[51]。腸道微生物通過多種途徑與大腦溝通，包括HPA軸、免疫調(diào)節(jié)、色氨酸和5-HT代謝及各種神經(jīng)活性化合物的產(chǎn)生，腸道微生物失調(diào)是抑郁癥重要誘因之一[52]。近期研究表明，ECS可以介導(dǎo)腸道微生物群誘發(fā)抑郁癥[53]，提示ECS信號(hào)的增強(qiáng)還有助于改善腸道微生物失調(diào)誘發(fā)的抑郁癥。綜上所述，ECS與抑郁癥的關(guān)聯(lián)機(jī)制可見圖1。

圖1 ECS與抑郁癥的關(guān)聯(lián)機(jī)制

3 中藥通過ECS調(diào)控抑郁癥的潛力

中醫(yī)藥治療抑郁癥有其獨(dú)特的優(yōu)勢，近年來，在中醫(yī)理論指導(dǎo)下，許多中藥被用于緩解和治療抑郁癥[54]。已有研究發(fā)現(xiàn)一些中藥復(fù)方、單味中藥和中藥有效成分具有介導(dǎo)ECS調(diào)控抑郁癥的潛力，提示從中藥中開發(fā)靶向ECS的抗抑郁藥物具有廣泛的研究前景。

3.1 中藥復(fù)方

在臨床上，曾有研究發(fā)現(xiàn)，每日口服菖郁逍遙方（石菖蒲10 g、郁金10 g、白芍10 g、茯苓15 g、柴胡10 g、當(dāng)歸10 g、薄荷6 g、炒白術(shù)15 g、炙甘草6 g）1劑，持續(xù)12周，可明顯改善慢性乙型肝炎伴抑郁癥患者的抑郁狀態(tài)[55]。值得注意的是，在治療抑郁癥患者的過程中，菖郁逍遙方顯著增加了患者血清中AEA、2-AG和CB1R水平，提示菖郁逍遙方的抗抑郁作用與ECS信號(hào)的增強(qiáng)有關(guān)。在臨床前研究中，網(wǎng)絡(luò)藥理學(xué)常被用于預(yù)測中藥及其復(fù)方發(fā)揮藥效的作用靶點(diǎn)，有研究采用該方法，預(yù)測了抗抑郁名方四逆散（由柴胡、白芍、枳實(shí)和炙甘草組成）的抗抑郁靶點(diǎn)[56]，結(jié)果表明，四逆散的抗抑郁作用可能與逆行內(nèi)源性大麻素信號(hào)的調(diào)節(jié)有關(guān)。另有報(bào)道還用網(wǎng)絡(luò)藥理學(xué)方法研究3種經(jīng)典行氣方劑（柴胡疏肝散、越鞠丸、半夏厚樸湯）的抗抑郁機(jī)制[57-58]，構(gòu)建了“化學(xué)成分-疾病”作用關(guān)系網(wǎng)絡(luò)，結(jié)果表明，這3種行氣復(fù)方也可能通過調(diào)節(jié)逆行內(nèi)源性大麻素來發(fā)揮抗抑郁作用，尚待進(jìn)一步驗(yàn)證。近期，有研究采用生物信息學(xué)結(jié)合實(shí)驗(yàn)驗(yàn)證的方法，探討經(jīng)典抗抑郁復(fù)方逍遙散（由柴胡、白芍、當(dāng)歸、白術(shù)、茯苓、炙甘草、生姜和薄荷組成）的抗抑郁機(jī)制[59]，結(jié)果顯示，2.2 g生藥/kg的逍遙散能夠顯著回調(diào)CUMS大鼠前額皮層中CB1R和CB2R基因mRNA的表達(dá)，從而增強(qiáng)ECS信號(hào)的傳遞，不僅如此，此研究最后還發(fā)現(xiàn)逍遙散的抗抑郁作用可能與CB1R/CB2R-cAMP-PKA-環(huán)磷腺苷效應(yīng)元件結(jié)合蛋白（cAMP-response element binding protein，CREB）-BDNF信號(hào)通路的激活有關(guān)。

3.2 單味中藥

厚樸具有良好的抗抑郁作用[60]，據(jù)報(bào)道，厚樸中的化學(xué)成分廣泛參與ECS的調(diào)控[61]，其中，主要活性成分和厚樸酚與厚樸酚可選擇性激活CB1R與CB2R，提示厚樸的抗抑郁作用可能通過ECS中大麻素受體的激活來實(shí)現(xiàn)。此外，具有抗抑郁作用的酸棗仁[62]和五味子[63]組成的藥對(duì)[酸棗仁-五味子（2∶1），1.5 g生藥/kg、3 g生藥/kg]能夠介導(dǎo)ECS-BDNF-ERK信號(hào)通路改善與抑郁癥發(fā)病機(jī)制相近的焦慮癥[64]，提示ECS的調(diào)控可能在酸棗仁和五味子的抗抑郁機(jī)制中同樣起著重要作用。最近，有研究采用網(wǎng)絡(luò)藥理學(xué)的方法剖析牛大力改善抑郁癥的作用機(jī)制[65]，研究顯示，CB1R可能是牛大力發(fā)揮抗抑郁作用的關(guān)鍵靶點(diǎn)，但需要進(jìn)一步驗(yàn)證。蜘蛛香的95%乙醇提取物具有良好的抗抑郁作用，最近的研究表明，40 mg/kg或80 mg/kg蜘蛛香的95%乙醇提取物還可以有效緩解小鼠的創(chuàng)傷后應(yīng)激障礙，并且與回調(diào)異常降低的CB1R、DAGL-α和異常增加的FAAH和MAGL有關(guān)[66]，創(chuàng)傷后應(yīng)激障礙與抑郁癥的病因和發(fā)病機(jī)制相似，提示蜘蛛香的抗抑郁作用可能與大麻素信號(hào)的增強(qiáng)也存在聯(lián)系。中藥之所以能產(chǎn)生抗抑郁作用，是因?yàn)橹兴幹泻写罅康奶烊豢挂钟艋钚猿煞諿67]，其中包含植物大麻素類化合物，如CBD，然而中藥中可能還有其他植物大麻素尚待發(fā)現(xiàn)。不久前，有研究采用無標(biāo)記表型動(dòng)態(tài)質(zhì)量再分配技術(shù)找到了靈芝中存在的4種新型大麻素（Kfb68、Kga1、Kfb28和Kfb77）[68]，其中，Kfb68可同時(shí)拮抗CB1R和CB2R，而Kga1和Kfb28對(duì)CB1R和CB2R有選擇性拮抗作用，Kfb77則是從靈芝中純化出的CB1R激動(dòng)劑，靈芝具有一定的抗抑郁作用[69]，提示靈芝的抗抑郁機(jī)制可能源于靈芝中天然外源性大麻素對(duì)抑郁癥機(jī)體ECS的調(diào)控，具體機(jī)制有待進(jìn)一步研究。

3.3 中藥有效成分

中藥活性成分的抗抑郁作用也有ECS的參與，曾有報(bào)道發(fā)現(xiàn)具有抗抑郁作用的姜黃素可以介導(dǎo)ECS信號(hào)發(fā)揮神經(jīng)調(diào)節(jié)作用[70]，150 mg/kg的姜黃素通過增加皮層、海馬、杏仁核、腦干中AEA和2-AG的水平來增強(qiáng)ECS信號(hào)的傳遞，進(jìn)而促進(jìn)大腦中神經(jīng)營養(yǎng)因子的釋放，提示姜黃素可能通過該途徑減輕抑郁癥引起的神經(jīng)損傷。早期研究還發(fā)現(xiàn)，肉豆蔻醚具有良好的抗抑郁效果，單次ip 3 mg/kg的肉豆蔻醚對(duì)行為絕望抑郁模型小鼠、利血平抑郁模型小鼠和慢性應(yīng)激抑郁模型小鼠均有顯著的抗抑郁作用，并且在強(qiáng)迫游泳實(shí)驗(yàn)中發(fā)現(xiàn)，CB1R和CB2R拮抗劑（AM251和AM630）能夠消除肉豆蔻醚的改善作用[71]，提示肉豆蔻醚的抗抑郁作用可能與大麻素受體的激活有關(guān)。另外，桂枝中主要成分反式肉桂醛的抗抑郁作用已被發(fā)現(xiàn)與ECS信號(hào)的調(diào)控有關(guān)[72]，研究表明，50 mg/kg的反式肉桂醛參與了抑郁模型小鼠海馬中COX-2、CB1R和TRPV1蛋白表達(dá)的調(diào)節(jié)。有趣的是，近期有研究表明萜烯和萜類化合物可能會(huì)增強(qiáng)大麻素對(duì)情緒障礙的治療活性，其中包括抑郁癥[73]，而藥用植物中富含具有抗抑郁作用的萜烯和萜類活性成分，如β-石竹烯[74]、芳樟醇和β-蒎烯[75]，其中，β-石竹烯（25 mg/kg）的抗抑郁作用已被發(fā)現(xiàn)與增加CB2R蛋白的表達(dá)有關(guān)[76]，提示中藥中萜烯和萜類活性成分是靶向ECS抗抑郁新藥的潛在開發(fā)來源。

當(dāng)前證據(jù)表明，中藥介導(dǎo)ECS發(fā)揮抗抑郁作用的途徑主要有2種，其一是中藥中含有植物大麻素類化合物，通過調(diào)節(jié)大麻素受體的活性來改善神經(jīng)損傷和免疫失調(diào)；另一方面是中藥通過提高內(nèi)源性大麻素的水平，進(jìn)而增強(qiáng)ECS對(duì)抑郁癥機(jī)體的保護(hù)作用，增加體內(nèi)內(nèi)源性大麻素水平的途徑可以是抑制代謝酶的活性，也可以是增強(qiáng)合成酶的功能。中藥介導(dǎo)ECS發(fā)揮抗抑郁作用的潛力可見圖2。

圖2 中藥介導(dǎo)ECS發(fā)揮抗抑郁作用的潛在途徑

4 結(jié)語與展望

植物大麻素曾被認(rèn)為是天然存在于大麻屬植物中的大麻素，然而，越來越多的天然大麻素被發(fā)現(xiàn)分布在大麻以外的物種中，中藥中新型大麻素的發(fā)現(xiàn)，源于中藥富含結(jié)構(gòu)和功能多樣性的化合物，中藥中天然大麻素的開發(fā)對(duì)大麻素庫存的完善[77]及抑郁癥的治療具有重要意義。除了植物大麻素，F(xiàn)AAH和MAGL抑制劑也被認(rèn)為是未來抑郁癥治療的新藥物[78]。總的來說，中藥中植物大麻素及ECS代謝酶抑制劑的探索是開發(fā)抗抑郁藥物的新策略。近年來，隨著CB1R和CB2R結(jié)構(gòu)的逐漸清晰及激活途徑和信號(hào)機(jī)制的不斷完善[79-81]，中藥中新型植物大麻素的尋找以及靶向ECS抗抑郁新藥的研發(fā)日益高效。

有趣的是，ECS信號(hào)曾被報(bào)道與嘌呤能信號(hào)存在相互作用，如嘌呤能信號(hào)中腺苷刺激的A1受體可介導(dǎo)CB1R參與神經(jīng)調(diào)節(jié)[82]，而CB1R的激活還能抑制嘌呤能P2X受體的生物學(xué)作用[83]；另有研究表明嘌呤能P2Y受體是內(nèi)源性大麻素的潛在靶點(diǎn)，發(fā)現(xiàn)P2Y1受體在內(nèi)源性大麻素抑制小膠質(zhì)細(xì)胞的炎癥反應(yīng)中起重要作用[84]。不僅如此，目前已有研究檢測到由CB1R與嘌呤能A2A受體構(gòu)成的聚合物[85]，可以共同控制Glu的釋放[86]。事實(shí)上，嘌呤能系統(tǒng)也已被證明與抑郁癥發(fā)病機(jī)制密切相關(guān)[87]，提示ECS和嘌呤能系統(tǒng)的相互作用可能在抑郁癥發(fā)病機(jī)制中起著關(guān)鍵作用。中藥在抑郁癥治療應(yīng)用中具有多靶點(diǎn)的優(yōu)勢，因此具備嘌呤能系統(tǒng)調(diào)節(jié)活性的中藥資源也是ECS調(diào)節(jié)劑的潛在研究對(duì)象。

利益沖突 所有作者均聲明不存在利益沖突

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Pathogenesis of depression based on endocannabinoid system and its application in traditional Chinese medicine research

CHEN Jia-jun1, 2, 3, QIN Xue-mei1, 2, 3, DU Guan-hua1, 4, ZHOU Yu-zhi1, 2, 3

1. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China 2. Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China 3. Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan 030006, China 4. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

Depression was a disease that was difficult to control, and satisfactory medication was lacking. From this perspective, the discovery of new pathogenesis for depression had important significance for the development of antidepressant drugs. In recent years, studies have found that depression was closely related to the disturbance of endocannabinoid system (ECS), but the mechanism involved was complex. At present, it was a new way to treat depression through the regulation of ECS, and traditional Chinese medicine had some natural advantages in this way. In this regard, the development of new antidepressant drugs had broad research prospects. In view of this, present study analyzed the relationship between ECS and depression, and also analyzed the antidepressant effects of ECS mediated by traditional Chinese medicine. The main purpose of this study was to provide a reference for the research of the pathogenesis of depression, and provide new strategies for the development of antidepressant drugs.

endocannabinoid system; depression; pathogenesis; phytocannabinoid; cannabinoid receptor

R28

A

0253 - 2670(2022)19 - 6273 - 10

10.7501/j.issn.0253-2670.2022.19.032

2022-06-07

國家自然科學(xué)基金面上項(xiàng)目（82074323）；國家自然科學(xué)基金面上項(xiàng)目（81673572）；國家重大新藥創(chuàng)制科技重大專項(xiàng)（2017ZX09301047）；山西省留學(xué)回國人員科技活動(dòng)擇優(yōu)資助項(xiàng)目（201991）；山西省回國留學(xué)人員科研資助項(xiàng)目（2020019）

陳佳俊（1997—），男，碩士研究生，研究方向?yàn)橹兴幩幚砑白饔脵C(jī)制。E-mail: chen_jiajun999@163.com

周玉枝，教授，博士生導(dǎo)師，研究方向?yàn)橹兴幩幮镔|(zhì)基礎(chǔ)及作用機(jī)制。Tel: (0351)7019178 E-mail: zhouyuzhi@sxu.edu.cn

[責(zé)任編輯 王文倩]