劉志國，王華林，王麗梅，劉烈炬

（武漢輕工大學(xué)生物與制藥工程學(xué)院，湖北 武漢 430023）

多不飽和脂肪酸對神經(jīng)細(xì)胞保護(hù)作用的研究進(jìn)展

劉志國，王華林，王麗梅，劉烈炬*

（武漢輕工大學(xué)生物與制藥工程學(xué)院，湖北 武漢 430023）

本文從細(xì)胞生物學(xué)的角度綜述多不飽和脂肪酸（polyunsaturated fatty acids，PUFAs）改善大腦功能的作用機(jī)理，包括PUFAs促進(jìn)神經(jīng)細(xì)胞生成（neurogenesis）、維持神經(jīng)細(xì)胞形態(tài)和功能、促進(jìn)神經(jīng)突生長、防止神經(jīng)細(xì)胞變性（neurodegeneration）、抑制神經(jīng)細(xì)胞凋亡（apoptosis），以及調(diào)節(jié)神經(jīng)細(xì)胞膜流動性和可塑性（plasticity）、端粒（telomere）活性等作用機(jī)制，為PUFAs的營養(yǎng)干預(yù)研究應(yīng)用，特別是應(yīng)用于保護(hù)大腦正常功能，防止生理性衰老和疾病性腦功能障礙（如阿爾茲海默氏癥和帕金森癥）所致的腦功能障礙提供參考。

多不飽和脂肪酸；神經(jīng)變性；神經(jīng)細(xì)胞；神經(jīng)發(fā)生；大腦功能

神經(jīng)細(xì)胞（也稱神經(jīng)元）是腦組織的主要功能細(xì)胞，其正常的生長分化及功能健全是維持大腦功能的基礎(chǔ)。多不飽和脂肪酸（polyunsaturated fatty acids，PUFAs）是一類在腦組織中含量豐富的脂肪酸，對維護(hù)神經(jīng)細(xì)胞的正常結(jié)構(gòu)和功能發(fā)揮著至關(guān)重要的作用[1-4]，尤其n-3 PUFAs具有促進(jìn)神經(jīng)細(xì)胞增殖、維持神經(jīng)細(xì)胞正常形態(tài)及促進(jìn)神經(jīng)突觸生長、防止神經(jīng)細(xì)胞變性與凋亡等功能作用，對促進(jìn)胎兒和嬰幼兒大腦的正常生長發(fā)育，防止老年期大腦功能的衰退具有重要作用[5-6]。本課題組前期探討了PUFAs對不同齡人群學(xué)習(xí)記憶功能的影響和對大腦功能的保護(hù)作用。同時(shí)，近年來國內(nèi)外也大量開展PUFAs增強(qiáng)大腦學(xué)習(xí)記憶等大腦功能的細(xì)胞學(xué)機(jī)制研究，取得了一些重要的進(jìn)展，包括PUFAs對大腦神經(jīng)細(xì)胞的形態(tài)和亞細(xì)胞結(jié)構(gòu)影響，對神經(jīng)細(xì)胞生成和神經(jīng)細(xì)胞變性及細(xì)胞凋亡的影響，以及對神經(jīng)細(xì)胞膜流動性、可塑性、端粒活性的調(diào)節(jié)作用等方面[3-5]。因此，細(xì)胞學(xué)機(jī)制研究已成為PUFAs增強(qiáng)大腦功能研究的重要內(nèi)容，并為進(jìn)一步闡明PUFAs的營養(yǎng)干預(yù)機(jī)制，拓寬其應(yīng)用領(lǐng)域提供了理論依據(jù)和重要參考。

1 PUFAs促進(jìn)神經(jīng)細(xì)胞生成

神經(jīng)細(xì)胞生成（或神經(jīng)發(fā)生）是神經(jīng)干細(xì)胞增殖、分裂成為定向祖細(xì)胞，并逐漸定向遷移、分化成為功能神經(jīng)細(xì)胞，構(gòu)成神經(jīng)系統(tǒng)的過程。腦組織中，通過神經(jīng)細(xì)胞生成作用，可增加大腦神經(jīng)元的數(shù)量，維護(hù)大腦的正常功能，而神經(jīng)細(xì)胞的生成與神經(jīng)干細(xì)胞（neural stem cell，NSC）的增殖、分化及遷移過程密不可分。神經(jīng)干細(xì)胞首先從成年小鼠側(cè)腦室膜下區(qū)分離獲得，隨后陸續(xù)在中樞神經(jīng)系統(tǒng)的多個(gè)部位（包括：大腦海馬區(qū)、大腦皮層和紋狀體等）分離獲得。例如，與大腦空間記憶功能有關(guān)的海馬神經(jīng)細(xì)胞，是由位于海馬顆粒細(xì)胞層和齒狀回門之間顆粒下層的海馬神經(jīng)干細(xì)胞經(jīng)歷增殖、分化，遷移至海馬CA1和CA3區(qū)形成[7]。盡管觀察到大腦的神經(jīng)生成能力可以持續(xù)到老年階段，但中年以后其生成能力急劇下降[8]。大量體內(nèi)和體外實(shí)驗(yàn)均表明PUFAs可促進(jìn)神經(jīng)細(xì)胞的生成，并能顯著延緩神經(jīng)細(xì)胞生成能力的衰退。例如，動物胚胎神經(jīng)發(fā)育期補(bǔ)充n-3 PUFAs可促進(jìn)神經(jīng)細(xì)胞的生成，增加神經(jīng)干細(xì)胞的增殖、分化成熟，但是n-6 PUFAs無此作用[9-12]。Fat1轉(zhuǎn)基因小鼠（可將n-6 PUFAs轉(zhuǎn)化為n-3 PUFAs的轉(zhuǎn)基因鼠），由于二十二碳六烯酸（docosahexaenoic acid，DHA）合成的大量增加，增加了神經(jīng)細(xì)胞生成的能力，并伴隨實(shí)驗(yàn)動物學(xué)習(xí)記憶能力的增強(qiáng)[13]。而且也發(fā)現(xiàn)，即使是老年實(shí)驗(yàn)動物，DHA仍具有促進(jìn)神經(jīng)干細(xì)胞分化的功能[14]，可通過促進(jìn)神經(jīng)干細(xì)胞的增殖和成熟，對老年大腦功能發(fā)揮保護(hù)作用。盡管在動物實(shí)驗(yàn)中觀察到n-3和n-6 PUFAs在保護(hù)大腦功能方面的顯著差異，但體外細(xì)胞培養(yǎng)實(shí)驗(yàn)顯示：n-3 PUFAs中的DHA或n-6 PUFAs中的花生四烯酸（arachidonic acid，AA）都可以促進(jìn)神經(jīng)干細(xì)胞的增殖[11,15]。這種體內(nèi)外作用的差異提示體內(nèi)微環(huán)境也是影響神經(jīng)細(xì)胞生成的重要因素。而且也有實(shí)驗(yàn)觀察到n-3 PUFAs缺乏的大鼠，腦源性神經(jīng)營養(yǎng)因子（brain-drived neurotrophic factor，BDNF）合成減少，神經(jīng)細(xì)胞生成受到抑制的現(xiàn)象[16]。到目前為止，PUFAs影響神經(jīng)細(xì)胞生成的機(jī)制并不十分清楚，綜合來看，其機(jī)制主要涉及：1）神經(jīng)干細(xì)胞的磷脂脂肪酸組成及其影響的細(xì)胞膜功能和膜蛋白定位是重要影響因素[17]；2）n-3 PUFAs及其活性衍生物通過相應(yīng)的信號轉(zhuǎn)導(dǎo)系統(tǒng)、膜相關(guān)途徑、核受體途徑等影響神經(jīng)細(xì)胞的功能[18]。

2 PUFAs促進(jìn)神經(jīng)突生長

PUFAs可以影響神經(jīng)細(xì)胞的形態(tài)，如增加細(xì)胞體積、促進(jìn)突觸的生長等[19]。神經(jīng)細(xì)胞體積的增加，常伴隨著神經(jīng)原纖維合成的增加以及神經(jīng)元功能的改變，還通常伴隨著神經(jīng)末梢和突觸結(jié)數(shù)量的增加[19-20]。神經(jīng)元核周質(zhì)的體積與神經(jīng)末梢密度，與大腦學(xué)習(xí)記憶功能之間表現(xiàn)為明顯的正相關(guān)的關(guān)系[21]。n-3 PUFAs作為神經(jīng)細(xì)胞膜的重要組成部分，可對細(xì)胞膜形成某種外凸壓力，促進(jìn)神經(jīng)細(xì)胞樹突棘形成，有助于神經(jīng)突起的生長和神經(jīng)突觸的生成[22]。神經(jīng)元形態(tài)變化，包括體積大小、神經(jīng)末梢分布以及突觸數(shù)量的改變是影響大腦神經(jīng)回路的關(guān)鍵因素，與大腦功能密切相關(guān)。如海馬神經(jīng)回路與大腦的學(xué)習(xí)記憶功能有著密切的聯(lián)系[23]。研究顯示，n-3 PUFAs中DHA的缺乏可導(dǎo)致海馬CA1區(qū)神經(jīng)元的萎縮，補(bǔ)充ɑ-亞麻酸（ɑ-linolenic acid，ALA）和DHA后，海馬CA1和CA3神經(jīng)元的體積增加[24]。其機(jī)制涉及蛋白激酶C（protein kinase C，PKC）的活化和海馬突觸小泡蛋白的表達(dá)增加[25-26]。

由于神經(jīng)突起和神經(jīng)細(xì)胞體積的變化往往聯(lián)系在一起，因此，當(dāng)神經(jīng)突生長時(shí)，總是首先表現(xiàn)為細(xì)胞體積和膜表面積的增加[27]。反過來也是這樣，當(dāng)海馬和下丘腦神經(jīng)元體積減小的同時(shí)，可以觀察到神經(jīng)元樹突分支的明顯減少[24]。研究表明DHA具有促進(jìn)海馬組織和大腦皮質(zhì)神經(jīng)元神經(jīng)突生長的作用[28]。在胚胎發(fā)育期，n-3 PUFAs的缺乏可導(dǎo)致神經(jīng)細(xì)胞突起的發(fā)育不良（突起少而短），而補(bǔ)充DHA可使細(xì)胞的突起的長度增加、數(shù)量增多，并伴隨著突觸蛋白含量的增加[29]；但n-6 PUFAs的AA在體內(nèi)沒有促進(jìn)神經(jīng)突生長的作用[30]。然而在體外培養(yǎng)細(xì)胞中觀察到，不管是n-6 PUFAs的亞油酸（linoleic acid，LA）、AA，還是n-3 PUFAs的ALA和DHA等，都可以促進(jìn)神經(jīng)突生長，只是飽和脂肪酸和單不飽和脂肪酸則無此作用[31-32]。這同樣提示，PUFAs對神經(jīng)突起和神經(jīng)細(xì)胞體積的影響與體內(nèi)微環(huán)境及代謝機(jī)制密切相關(guān)。有研究顯示DHA可能通過其代謝物N-二十二碳六烯乙醇胺（N-docosahexaenoylethanolamide，DEA）發(fā)揮作用，并通過G-蛋白受體促進(jìn)神經(jīng)干細(xì)胞分化和神經(jīng)突起生長[33-34]。另外，PUFAs可能作用于神經(jīng)生長因子（nerve growth factor，NGF）[35]，從而促進(jìn)神經(jīng)細(xì)胞生長發(fā)育[24,36]。大腦n-3 PUFAs的缺乏，可導(dǎo)致海馬組織NGF含量顯著的下降。在NGF的刺激下，通過磷脂酶A2（phospholipase A2，PLA2）的作用，可導(dǎo)致AA和DHA從細(xì)胞膜的釋放。被釋放的AA和DHA可與突觸融合蛋白3結(jié)合，在可溶性N-乙?；R來酰亞胺敏感因子結(jié)合蛋白受體（soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor，SNAREs）的協(xié)助下，導(dǎo)致膜磷脂雙層結(jié)構(gòu)的融合，促進(jìn)神經(jīng)突的生長。

雖然單獨(dú)補(bǔ)充DHA可增加神經(jīng)元樹突棘和突觸的數(shù)量[37]。但實(shí)驗(yàn)觀察到DHA與尿苷、膽堿聯(lián)合干預(yù)具有明顯的協(xié)同效應(yīng)，可顯著增加DHA對神經(jīng)細(xì)胞生長分化的作用[38]。由于尿苷、膽堿和PUFAs是合成磷脂的主要成分。因此，三者的合并使用可進(jìn)一步促進(jìn)大腦磷脂，以及多種突觸蛋白的合成。實(shí)驗(yàn)顯示：在沙鼠的飼料中進(jìn)行尿苷、膽堿和DHA的聯(lián)合干預(yù)，可使突觸小泡突觸蛋白-1（synapsin-1）含量增加41%，突觸后蛋白質(zhì)psd-95增加38%，突觸的神經(jīng)纖維蛋白-M（neurofibrillar protein-M，NF-M）和神經(jīng)纖維蛋白-70（neurofibrillar protein-70，NF-70）分別增加48%和102%[38]。上述結(jié)果表明：尿苷、膽堿、AA和DHA的聯(lián)合干預(yù)是增加PUFAs功能的有效途徑。尿苷的食物來源常見的有：番茄和西蘭花。富含膽堿的食物包括：雞蛋、鱈魚、小麥胚芽、花椰菜、菠菜、藜麥等。母乳含有豐富的尿苷、膽堿、AA和DHA等成分[39]，是嬰兒智力發(fā)育最好的食物來源。

3 PUFAs防止神經(jīng)變性

神經(jīng)變性（neurodegeneration）和壞死（necrosis）是造成神經(jīng)細(xì)胞數(shù)量減少的重要原因之一。PUFAs可通過抗神經(jīng)變性的作用，防止神經(jīng)細(xì)胞數(shù)量減少，維護(hù)正常的大腦學(xué)習(xí)記憶功能。影響神經(jīng)變性的因素眾多，主要包括常見的環(huán)境因素和機(jī)體自身的生理、病理性因素。前者包括化學(xué)（如酒精和環(huán)境污染）、物理（機(jī)械損傷、電離輻射和噪音等）、生物（病毒和細(xì)菌感染等）等因素；后者主要有衰老、精神因素（緊張和抑郁等）和神經(jīng)變性疾病或稱神經(jīng)退行性疾病等。在防范有害的環(huán)境因素基礎(chǔ)上，營養(yǎng)干預(yù)延緩生理或病理性神經(jīng)變性損傷對維護(hù)大腦功能尤為重要。大量研究表明[2-3,40-43]：PUFAs，特別是長鏈（long chain，LC）-PUFAs，在防止神經(jīng)細(xì)胞變性的過程中，發(fā)揮著重要的作用。

3.1 PUFAs防止衰老導(dǎo)致的神經(jīng)細(xì)胞變性

在生理特征上，衰老表現(xiàn)為感官、運(yùn)動和認(rèn)知功能的下降，是導(dǎo)致神經(jīng)變性重要生理因素[44]。隨著機(jī)體的衰老，血漿中n-3 PUFAs的含量逐漸下降，n-3 PUFAs含量的下降反過來又進(jìn)一步促進(jìn)機(jī)體的衰老[41]。研究發(fā)現(xiàn)大腦中的總脂質(zhì)的含量，特別是DHA的含量，與大腦的功能和神經(jīng)變性密切相關(guān)。在生命的開始20 a里，大腦脂質(zhì)的含量呈逐漸增加的趨勢，隨后保持基本的穩(wěn)定，老年后脂質(zhì)的含量快速下降[45]。衰老造成大腦功能損傷有兩個(gè)常見的原因：一是神經(jīng)細(xì)胞的喪失（包括神經(jīng)細(xì)胞的凋亡和壞死）；二是神經(jīng)細(xì)胞結(jié)構(gòu)和功能的變化，即神經(jīng)變性。研究表明[46-47]，在大腦衰老過程中實(shí)際死亡神經(jīng)細(xì)胞的數(shù)量并不多，造成大腦功能衰退的主要原因是由于年齡增長導(dǎo)致的神經(jīng)細(xì)胞結(jié)構(gòu)和功能的改變，表現(xiàn)為神經(jīng)遞質(zhì)釋放的減少和傳遞功能的下降等。而腦內(nèi)氧化物的增加，細(xì)胞解毒功能的下降是導(dǎo)致神經(jīng)變性的重要原因[48]。PUFAs則可以保護(hù)和防止這一過程，通過增加機(jī)體抗氧化能力，阻止活性氧（reactive oxygen species，ROS）的增加，促進(jìn)樹突重塑，防止大腦興奮性中毒所致的大腦功能紊亂[45]，從而對抗神經(jīng)變性，增加大腦學(xué)習(xí)記憶的能力[49-50]。進(jìn)一步研究發(fā)現(xiàn)[51-52]：食物中的二十碳五烯酸（eicosapentaenoic acid，EPA）和DHA可以緩解衰老過程中大腦中PUFAs含量的下降，提高年齡相關(guān)的谷氨酸受體中的N-甲基-D-天冬氨酸受體2B（N-methyl-D-aspartate receptor 2B，NR2B）亞單位和α-氨基-3-羧基-5-甲基異唑-4-丙酸（alpha-amino-3-hydoxy-5-methyl-4-isoxazolepropionate，AMPA）受體的谷氨酸受體2（glutamate receptor 2，GluR2）亞單位的表達(dá)，并增加大腦的學(xué)習(xí)記憶功能。這些受體在神經(jīng)變性的過程中起著重要的作用，除直接參與突觸的傳遞功能外，GluR2還在促進(jìn)樹突增長和維持樹突棘穩(wěn)定中扮演著重要的角色[53]。

3.2 PUFAs改善細(xì)胞膜的功能，防止神經(jīng)變性

突觸的可塑性被廣泛認(rèn)為是大腦功能最重要的細(xì)胞結(jié)構(gòu)基礎(chǔ)[45]。許多研究探討了與年齡相關(guān)的突觸可塑性變化和大腦認(rèn)知功能障礙之間的相關(guān)性，研究發(fā)現(xiàn)影響記憶形成的主要因素可能是突觸可塑性的變化，而影響記憶喪失（遺忘）的主要因素是突觸功能衰退[54-55]。年齡的增長可導(dǎo)致記憶形成的閾值增加，記憶喪失的閾值減小[56]。AA和DHA是神經(jīng)細(xì)胞質(zhì)膜（包括細(xì)胞膜、線粒體膜、蘘泡膜等）的重要組成部分，在突觸部位其含量可達(dá)摩爾水平[18]。AA和DHA在神經(jīng)細(xì)胞質(zhì)膜水平的改變可直接影響到細(xì)胞膜的特性（包括膜的流動性、曲率和脂質(zhì)筏的形成等），進(jìn)一步影響鑲嵌在脂質(zhì)雙層中蛋白質(zhì)的功能（包括受體、通道和酶類等），因此PUFAs在維持突觸可塑性中發(fā)揮了關(guān)鍵的作用。食物中的PUFAs，有利于緩解由衰老導(dǎo)致的大腦AA和DHA水平的下降，對抗由衰老導(dǎo)致的神經(jīng)細(xì)胞結(jié)構(gòu)和功能的變化，增強(qiáng)大腦學(xué)習(xí)記憶的功能[57]。

膜的流動性受多方面因素的影響。飲食習(xí)慣可以直接影響神經(jīng)元膜脂肪酸組成。實(shí)驗(yàn)證明通過補(bǔ)充PUFAs可以改善膜流動性，進(jìn)而影響突觸的可塑性，神經(jīng)傳遞和突觸生成，增強(qiáng)學(xué)習(xí)記憶的能力[55,57]。膜流動性也受到年齡和神經(jīng)變性疾病的影響，如阿爾茨海默?。ˋlzheimer’s disease，AD）和帕金森?。≒arknson’s disease，PD）。影響膜流動性的其他原因包括：膽固醇和活性氧含量的增加[58]?；钚匝蹩蓪?dǎo)致膜蛋白和脂質(zhì)化學(xué)交聯(lián)，減少細(xì)胞膜的不飽和性。這除了可降低膜流動性外，還可導(dǎo)致膜中酶、離子通道和受體的抑制[59]。增加PUFAs的攝入量可以部分對抗ROS的作用，但大劑量的使用仍然值得注意[58]。n-3 PUFAs結(jié)合入神經(jīng)膜，可降低細(xì)胞膜膽固醇的含量、改善神經(jīng)細(xì)胞膜的特性，例如流動性、滲透性和黏度等，同時(shí)改善神經(jīng)傳遞、突觸可塑性、學(xué)習(xí)記憶及其他復(fù)雜的認(rèn)知過程[2,6,40]。

PUFAs影響膜流動性的機(jī)制之一，是通過抑制脂質(zhì)筏（膜質(zhì)雙層含中由特殊的脂質(zhì)和蛋白質(zhì)組成的微區(qū)，該區(qū)域結(jié)構(gòu)致密，屬抗去垢劑的膜組分[60]，富含膽固醇、鞘磷脂、糖脂，是蛋白質(zhì)停泊的平臺，與膜的信號轉(zhuǎn)導(dǎo)、蛋白質(zhì)的分選有關(guān)系密切）的形成和跨膜受體蛋白的定位和表達(dá)來完成的。脂質(zhì)雙層的磷脂中DHA的含量增加，導(dǎo)致脂質(zhì)雙層更加松散，更多的流動性和可壓縮性以及更強(qiáng)的滲透性。此外DHA還具有排斥膽固醇的作用。DHA取代膜內(nèi)的飽和脂肪酸后，造成該區(qū)域內(nèi)膽固醇的濃度降低，從而干擾脂筏的形成[61]。實(shí)驗(yàn)證明膳食中補(bǔ)充ALA并不能改變膜磷脂分布，然而補(bǔ)充DHA可以明顯提高細(xì)胞膜磷脂的水平[62]。雖然DHA可迅速結(jié)合入脂質(zhì)雙層結(jié)構(gòu)中的磷脂，但在各類磷脂之間分布是不均勻的。DHA優(yōu)先結(jié)合入sn-2位置磷脂酰乙醇胺（phosphatidylethanolamine，PE）以及少量的磷脂酰膽堿（phosphatidyl choline，PC）或磷脂酰絲氨酸（phosphatidylserine，PS）[63-65]。在大腦，DHA結(jié)合在磷脂酰絲氨酸磷脂中可促進(jìn)信號轉(zhuǎn)導(dǎo)分子蛋白激酶B（protein kinase B，PKB)（也稱AKT）向細(xì)胞核的易位，調(diào)節(jié)凋亡基因的轉(zhuǎn)錄[66]。另外，PUFAs還可調(diào)節(jié)細(xì)胞膜的硬度，導(dǎo)致巨噬細(xì)胞黏度增加和對凋亡細(xì)胞的吞噬作用的下降[62,67]。

3.3 PUFAs調(diào)節(jié)端粒的長度，延緩大腦功能衰退

神經(jīng)細(xì)胞的衰老死亡可導(dǎo)致神經(jīng)元的數(shù)量減少，影響大腦的功能。關(guān)于細(xì)胞的衰老目前有多種學(xué)說，最重要是內(nèi)置時(shí)鐘說、氧化應(yīng)激說和端粒學(xué)說[45]。端粒學(xué)說提出細(xì)胞的衰老源于端?？s短。端粒是真核細(xì)胞染色體兩臂末端由5′TTAGGG-3′重復(fù)序列構(gòu)成的結(jié)構(gòu)，具有保護(hù)染色體末端，維持染色體結(jié)構(gòu)的穩(wěn)定和完整、避免其發(fā)生融合、降解、重組等功能。端粒的長度與衰老、認(rèn)知能力（包括學(xué)習(xí)記憶能力）、以及老年性疾病的發(fā)生（如癡呆和神經(jīng)退行性疾?。┯兄芮械年P(guān)系[68-69]，并受多種因素的影響，如：炎性反應(yīng)和氧化應(yīng)激反應(yīng)等[70-72]。體育鍛煉、他汀類藥物（用于治療高膽固醇血癥）、補(bǔ)充n-3 PUFAs等可增加端粒的長度，延緩衰老，其機(jī)制可能與端粒酶的活性變化有關(guān)[73]。

端粒的長度受到飲食中脂肪酸組成的影響。最近一項(xiàng)研究將實(shí)驗(yàn)分為飽和脂肪酸組、低脂高糖組和地中海飲食組（富含單不飽和脂肪酸）三組，通過隨機(jī)交叉分析發(fā)現(xiàn)地中海飲食組細(xì)胞內(nèi)活性氧的水平、細(xì)胞凋亡數(shù)和端粒的縮短都明顯低于脂肪酸組和低脂高糖組[71]。PUFAs對端粒的長度也有影響，且發(fā)現(xiàn)n-6和n-3 PUFAs對端粒的作用是不同的。n-3 PUFAs可延緩端?？s短，而n-6 PUFAs可能會加速端粒的縮短，因此在實(shí)驗(yàn)中應(yīng)區(qū)分n-3和n-6脂肪酸的作用[74]。最近采用前瞻性隊(duì)列研究對冠狀動脈疾病的患者追蹤調(diào)查后發(fā)現(xiàn)，血液中n-3 PUFAs的含量與端?？s短的速率成負(fù)相關(guān)的關(guān)系[75]。O’Callaghan等[68]在對輕度認(rèn)知障礙（mild cognitive impairment，MCI）老年人補(bǔ)充n-3 PUFAs時(shí)發(fā)現(xiàn)，雖然干預(yù)與治療組端粒長度沒有顯著的變化，但血液中的紅細(xì)胞DHA的水平與端?？s短密切相關(guān)，即紅細(xì)胞DHA含量增加端?？s短的速率降低，提示n-3 PUFAs可能延緩端粒的縮短，且n-3脂肪酸對端粒的影響與n-6/n-3的比例有關(guān)。Kiecolt-glaser等[72]研究采用隨機(jī)對照實(shí)驗(yàn)探討了n-3 PUFAs的干預(yù)，與白細(xì)胞端粒長度、促炎細(xì)胞因子和氧化應(yīng)激的關(guān)系，發(fā)現(xiàn)n-3 PUFAs可降低血液中促炎細(xì)胞因子的濃度和氧化應(yīng)激的水平，降低n-6/n-3 PUFAs的比值可導(dǎo)致端粒長度增加，提示飲食中n-6/n-3 PUFAs比值對延緩大腦功能衰退的重要作用，表明n-3 PUFAs與n-6 PUFAs對炎性應(yīng)激和氧化應(yīng)激存在作用差異，從而對端粒長度的影響不一致。雖然PUFAs對端粒的作用以及與大腦功能的關(guān)系目前仍缺乏足夠的資料，但為PUFAs的功能作用與機(jī)理研究提供了新的方向[76]。

3.4 PUFAs干預(yù)疾病所致的神經(jīng)變性

神經(jīng)變性疾病是影響神經(jīng)變性的重要的病理因素。神經(jīng)變性疾病是一組原因不明的，以神經(jīng)細(xì)胞變性為主要的病理特征的中樞神經(jīng)系統(tǒng)疾病，典型的如AD和PD[41]。

AD是以進(jìn)行性癡呆為主要臨床表現(xiàn)的大腦變性疾病，俗稱老年癡呆癥。研究發(fā)現(xiàn)AD的發(fā)病與腦內(nèi)β淀粉樣蛋白（Aβ）異常沉淀有關(guān)。Aβ的前體是前β淀粉樣蛋白，由于三級結(jié)構(gòu)中的β折疊，形成了不可溶的特性。研究發(fā)現(xiàn)Aβ對周圍的突觸和神經(jīng)元具有毒性作用，可導(dǎo)致神經(jīng)細(xì)胞變性死亡[77]。隨著神經(jīng)元的變性死亡，導(dǎo)致腦內(nèi)相應(yīng)的神經(jīng)遞質(zhì)水平下降，其中最重要的是乙酰膽堿。由于AD患者中腦內(nèi)的乙酰膽堿的水平下降得最早和最為明顯，因此產(chǎn)生了AD的膽堿能學(xué)說：即AD患者乙酰膽堿的缺乏是導(dǎo)致認(rèn)知功能障礙的主要因素。增加腦內(nèi)乙酰膽堿的水平是目前AD藥物治療的重要手段。例如，采用膽堿酯酶抑制劑，通過抑制乙酰膽堿的酶解，增加膽堿能神經(jīng)元的傳遞功能。但這些擬膽堿類藥物，雖然能緩解患者認(rèn)知能力的下降，但并不能延緩AD的病程的發(fā)展。

研究表明[78-80]，AD的發(fā)病與機(jī)體能量代謝失衡有關(guān)，且氧化應(yīng)激和線粒體功能障礙在AD的發(fā)病機(jī)制中扮演著重要的角色，是藥物治療AD新的潛在的靶標(biāo)。線粒體功能障礙是導(dǎo)致β樣淀粉樣變的重要病因[81-84]。DHA可抑制前淀粉樣蛋白轉(zhuǎn)化為Aβ，并阻止Aβ的累積[85-86]。DHA可對抗Aβ引起的神經(jīng)毒性反應(yīng)，對大腦產(chǎn)生保護(hù)作用[87]。在人胚腎-淀粉酶前體蛋白（human embryonic kidney-amyloid precursor protein，HEK-APP）細(xì)胞，DHA可顯著提高膜流動性、增加可溶性淀粉酶前體蛋白α（soluble amyloid precursor protein α，sAPPα）的分泌。后者具有對線粒體的保護(hù)作用以及抗凋亡的功能[88]。動物實(shí)驗(yàn)表明[86,89-90]：富含DHA的飲食可以減少老年癡呆癥小鼠模型中Aβ的含量。對老年3hTg-AD小鼠（大腦中含有大量Aβ的模型鼠）補(bǔ)充DHA，可導(dǎo)致膜磷脂內(nèi)DHA水平增加、AA含量降低以及心磷脂水平增加；并明顯改善大腦的認(rèn)知能力和內(nèi)嗅皮層神經(jīng)元的功能障礙[91-92]。大量研究顯示[85]，減少n-3 PUFAs的攝入量或魚類食品的消費(fèi)，可增加與年齡相關(guān)的認(rèn)知能力的下降或患呆癡癥的風(fēng)險(xiǎn)。

PD又稱為振顫麻痹癥，是一種與年齡相關(guān)的慢性和進(jìn)行性的神經(jīng)變性疾病。主要的臨床特征是運(yùn)動障礙，伴隨著大腦認(rèn)知能力的下降和精神癥狀，病理特征為大腦黑質(zhì)致密部（substantia nigra pars compacta，SNPC）多巴胺能神經(jīng)元的廣泛的變性死亡[93]。在尸檢報(bào)告中，大腦SNPC勻漿DHA水平明顯下降[94]。尸檢結(jié)果還表明PD患者額葉皮層脂質(zhì)筏的分離體中DHA和AA的含量大幅下降[95]。氧化應(yīng)激是PD重要的發(fā)病機(jī)制。在PD腦內(nèi)發(fā)現(xiàn)，脂質(zhì)過氧化物水平，黑質(zhì)和紋狀體中8-OHdG（8-羥脫氧鳥苷，DNA氧化損傷的標(biāo)志物）的含量以及亞硝?；偷鞍踪|(zhì)碳酰基水平均明顯的增加。進(jìn)一步可導(dǎo)致線粒體功能障礙，誘導(dǎo)細(xì)胞變性和凋亡，最終導(dǎo)致多巴胺能神經(jīng)元的死亡。

攝入DHA膠囊可選擇性地增加小鼠額葉皮層DHA的水平，阻斷由1-甲基-4-苯基吡啶離子（1-methyl-4-phenyl-pyridinium，MPP+）導(dǎo)致黑質(zhì)細(xì)胞數(shù)量的下降以及核受體相關(guān)因子1（nuclear receptor-related factor 1，Nurr1）mRNA和多巴胺轉(zhuǎn)運(yùn)體mRNA水平的下降[96]。Nurr1是多巴胺能神經(jīng)元重要轉(zhuǎn)錄因子[97]。飲食中的DHA可對抗由MPP+導(dǎo)致的紋狀體多巴胺及其代謝物二羥基苯乙酸（dihydroxyphenylacetic acid）含量的下降[96]。在MPP+誘導(dǎo)的PD模型中，DHA治療可緩解PD部分神經(jīng)癥狀[98-99]。采用MPP+PD模型，實(shí)驗(yàn)探討了LC-PUFAs對左旋多巴（levodopa，LD）誘導(dǎo)運(yùn)動障礙的影響，DHA可對抗LD誘導(dǎo)運(yùn)動障礙或延遲運(yùn)動障礙的發(fā)展[100]。在1-甲基-4-苯基-1,2,3,6-四氫吡啶（1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine，MPTP）-丙磺舒（probenecid）PD小鼠的模型中，飲食補(bǔ)充乙基-EPA后，可預(yù)防運(yùn)動功能減退和記憶力的改善，但不能阻止黑質(zhì)紋狀體多巴胺的下降[101]。在小鼠和大鼠PD模型中，腦室注射6-羥多巴胺（6-hydroxydopamine，6-OHDA）可引起紋狀體病變，包括多巴胺的水平下降[102-103]?？诜﨑HA可對抗6-OHDA的作用，部分恢復(fù)多巴胺能神經(jīng)傳遞功能[103]。老鼠腹腔內(nèi)注射乙基-DNA，也可對抗6-OHDA導(dǎo)致小鼠紋狀體多巴胺的水平下降[102]。大量文獻(xiàn)均表明高n-3 LC-PUFAs的飲食對預(yù)防或緩解PD具有顯著作用[96,98,100,104]。

4 PUFAs對神經(jīng)細(xì)胞凋亡的影響

PUFAs對細(xì)胞凋亡的影響是目前營養(yǎng)生物學(xué)研究的重要領(lǐng)域[22,88,105-106]。PUFAs的抗凋亡功能與n-3 PUFAs的抗炎、抗氧化有關(guān)，并對大腦具有保護(hù)作用，包括嬰幼兒大腦的發(fā)育、老年大腦的衰老以及神經(jīng)變性疾病等[22,106]。n-3 PUFAs可通過抗凋亡的作用，保持一定神經(jīng)元的數(shù)量，維持神經(jīng)系統(tǒng)的正常功能。

PUFAs的抗凋亡功能目前已有許多文獻(xiàn)的報(bào)道。最新研究表明孕婦和產(chǎn)婦飲食中的DHA有助于預(yù)防由產(chǎn)前精神壓力導(dǎo)致新生兒記憶功能的障礙，氧化標(biāo)記物含量的增加，線粒體代謝功能紊亂以及海馬細(xì)胞的凋亡[107]。同時(shí)，產(chǎn)前n-3 PUFAs的干預(yù)可對抗高氧血癥誘導(dǎo)大鼠大腦細(xì)胞的凋亡[108]。懷孕期間食用富含DHA的食物，可以通過抑制氧化應(yīng)激和細(xì)胞的凋亡，減少新生兒大腦的損傷[109]。新生兒的高血膽紅素血癥所致的血清未結(jié)合膽紅素（unconjugated bilirubin，UCB）水平升高，可對中樞神經(jīng)系統(tǒng)造成各種副作用。DHA的干預(yù)可對抗UCB導(dǎo)致的超氧化物歧化酶（superoxide dismutase，SOD）、過氧化氫酶以及谷胱甘肽過氧化物酶（glutathione peroxidase，GPX）活性下降；以及UCB誘導(dǎo)的星形細(xì)胞的凋亡，表明DHA可通過抑制細(xì)胞的凋亡和增加抗氧化酶的活性，對大腦細(xì)胞產(chǎn)生保護(hù)作用[110]。在大腦的生長發(fā)育期間，充足的n-3 PUFAs也可以通過抑制感光細(xì)胞凋亡和視網(wǎng)膜的變性，對視網(wǎng)膜產(chǎn)生保護(hù)作用[111-113]。氧化損傷和線粒體功能失調(diào)是導(dǎo)致神經(jīng)細(xì)胞凋亡的重要因素，DHA可激活細(xì)胞內(nèi)多種調(diào)節(jié)機(jī)制、抑制氧化應(yīng)激反應(yīng)、維護(hù)線粒體的功能、提高抗凋亡蛋白-B淋巴細(xì)胞瘤-2（B-cell lymphoma-2，Bcl-2）的含量，保護(hù)神經(jīng)細(xì)胞免受到傷害[111-112]。

PUFAs的抗凋亡作用是一個(gè)復(fù)雜的過程，多種信號轉(zhuǎn)導(dǎo)系統(tǒng)參與了PUFAs的抗凋亡過程，如細(xì)胞內(nèi)Ca2+信號系統(tǒng)、磷脂酰肌醇(-3)激酶/蛋白激酶B（phosphatidylinositol (-3) kinase/protein kinase B，PI3K/Akt）途徑、細(xì)胞外調(diào)節(jié)蛋白激酶（extracellular regulated protein kinases，ERK）/絲裂原活化蛋白激酶（mitogenactivated protein kinases，MAPKs）途徑和P38蛋白激酶（mitogen-activated protein kinases p38，P38MAPKs）途徑等。機(jī)理涉及docosanoid類脂質(zhì)信號分子的作用、線粒體在抗凋亡過程中的作用以及表觀遺傳學(xué)效應(yīng)等。

綜上所述，近年來開展的PUFAs對神經(jīng)細(xì)胞保護(hù)作用研究取得了很多成果，并注意到不同類型PUFAs對神經(jīng)細(xì)胞結(jié)構(gòu)與功能影響存在差異。其中n-3 PUFAs展現(xiàn)了較為全面的有益作用和獨(dú)特的細(xì)胞學(xué)機(jī)制，歸納起來包括：通過促進(jìn)神經(jīng)細(xì)胞增殖分化、增加神經(jīng)細(xì)胞的數(shù)量；通過抗氧化、抗凋亡及阻止端?？s短等機(jī)制防止生理或病理?xiàng)l件下的神經(jīng)細(xì)胞變性；以及通過影響神經(jīng)細(xì)胞的膜可塑性和突觸功能，維護(hù)神經(jīng)細(xì)胞的正常結(jié)構(gòu)與功能，實(shí)現(xiàn)對大腦的保護(hù)作用（圖1）。這些機(jī)制研究為PUFAs尤其是其中的n-3 PUFAs保護(hù)大腦功能的營養(yǎng)干預(yù)奠定了重要的細(xì)胞生物學(xué)基礎(chǔ)。

圖1 PUFAs保護(hù)大腦功能的細(xì)胞生物學(xué)機(jī)制示意圖Fig.1 Schematic diagram of the mechanism of action of PUFAs in protecting brain function

5 結(jié) 語

近年來，有關(guān)PUFAs對大腦功能的保護(hù)作用研究已取得了豐碩成果，發(fā)現(xiàn)PUFAs不僅可以通過抗炎、抗氧化、維護(hù)心腦血管功能等全身性功能，改善大腦的微環(huán)境而發(fā)揮對大腦的保護(hù)作用；而且揭示了其直接作用于神經(jīng)細(xì)胞，促進(jìn)神經(jīng)細(xì)胞生長和突觸的形成，以及通過調(diào)節(jié)細(xì)胞膜流動性和可塑性，保護(hù)神經(jīng)細(xì)胞正常功能。展望未來，研究將不斷深入到細(xì)胞與分子水平，從細(xì)胞生物學(xué)與分子生物學(xué)角度揭示其對神經(jīng)細(xì)胞作用的分子機(jī)制。特別是關(guān)于PUFAs及其活性代謝物調(diào)節(jié)細(xì)胞信號轉(zhuǎn)導(dǎo)系統(tǒng)、膜相關(guān)途徑、核受體途徑，促進(jìn)神經(jīng)細(xì)胞生成、突觸生長，阻止細(xì)胞變性和凋亡的細(xì)胞內(nèi)途徑與作用機(jī)制，從而發(fā)揮其延緩大腦功能衰退與神經(jīng)變性類疾病發(fā)展的有益作用，為PUFAs的營養(yǎng)功能及其對大腦功能的保護(hù)作用研究奠定基礎(chǔ)。

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Advances in Research on Neuron-Protective Role of Polyunsaturated Fatty Acids

LIU Zhiguo, WANG Hualin, WANG Limei, LIU Lieju*
(School of Biology and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430023, China)

The protective effects of polyunsaturated fatty acids (PUFAs) on brain function and the nervous system have attracted a lot of attention. Numerous studies have illustrated the anti-inflammation, anti-oxidative and cardiovascular protective effects of PUFAs, as well as the protective effects on brain function, particularly nerve cells. In this article, we review the mechanisms of brain-protective effects of PUFAs in following fields： how PUFAs promote neurogenesis，maintain nerve cell morphology and function, improve neurite growth; prevent neurodegeneration, depress nerve cell apoptosis and regulate membrane fluidity， plasticity and telomere activity in neurons. This review provides a prospective insight on nutritional studies of PUFAs against aging and/or diseases (such as Alzheimer’s disease and Parkinson’s disease) inducing brain disorders.

polyunsaturated fatty acid; neurodegeneration; nerve cells; neurogenesis; brain function

10.7506/spkx1002-6630-201607043

TS201.4

A

1002-6630（2016）07-0239-10

劉志國, 王華林, 王麗梅, 等. 多不飽和脂肪酸對神經(jīng)細(xì)胞保護(hù)作用的研究進(jìn)展[J]. 食品科學(xué), 2016, 37(7): 239-248. DOI:10.7506/spkx1002-6630-201607043. http://www.spkx.net.cn

LIU Zhiguo, WANG Hualin, WANG Limei, et al. Advances in research on neuron-protective role of polyunsaturated fatty acids[J]. Food Science, 2016, 37(7): 239-248. (in Chinese with English abstract) DOI:10.7506/spkx1002-6630-201607043. http://www.spkx.net.cn

2015-03-26

國家自然科學(xué)基金面上項(xiàng)目（31271855）；國家自然科學(xué)基金青年科學(xué)基金項(xiàng)目（31000772）；湖北省自然科學(xué)基金項(xiàng)目（2014CFB887）；湖北省教育廳科技計(jì)劃項(xiàng)目（D20141705）

劉志國（1963—），男，教授，博士，研究方向?yàn)闋I養(yǎng)與食品安全。E-mail：zhiguo_l@126.com

*通信作者：劉烈炬（1952—），男，教授，碩士，研究方向?yàn)闋I養(yǎng)生物學(xué)。E-mail：liulieju@qq.com