250355　濟(jì)南，山東中醫(yī)藥大學(xué)基礎(chǔ)醫(yī)學(xué)院[趙海軍　王　媛　韓冰冰]，針推學(xué)院(盧　巖)，國(guó)際教育學(xué)院[王世軍(通信作者)]；齊魯工業(yè)大學(xué)化學(xué)與制藥工程學(xué)院(李　燕)

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星形膠質(zhì)細(xì)胞對(duì)神經(jīng)元能量代謝的影響

趙海軍李燕盧巖王媛韓冰冰王世軍

250355濟(jì)南，山東中醫(yī)藥大學(xué)基礎(chǔ)醫(yī)學(xué)院[趙海軍王媛韓冰冰]，針推學(xué)院(盧巖)，國(guó)際教育學(xué)院[王世軍(通信作者)]；齊魯工業(yè)大學(xué)化學(xué)與制藥工程學(xué)院(李燕)

【DOI】10.3969/j.issn.1007-0478.2015.06.020

在神經(jīng)系統(tǒng)中膠質(zhì)細(xì)胞約占細(xì)胞總數(shù)的90%，其中星形膠質(zhì)細(xì)胞是其主要的組成部分，其數(shù)量約為神經(jīng)元數(shù)量的5倍。過去一直認(rèn)為大腦中只有神經(jīng)元具有傳遞和處理信息的功能，而星形膠質(zhì)細(xì)胞只對(duì)神經(jīng)元起營(yíng)養(yǎng)、支持、保護(hù)及絕緣的作用。但近年來的研究發(fā)現(xiàn)，星形膠質(zhì)細(xì)胞在調(diào)節(jié)神經(jīng)元能量代謝等方面也起到了至關(guān)重要的作用，逐漸成為了神經(jīng)科學(xué)研究的熱點(diǎn)[1]。

1星形膠質(zhì)細(xì)胞對(duì)神經(jīng)元葡萄糖代謝的影響

大腦的能量需求非常旺盛，盡管只占體重的2%，腦組織卻消耗了20%的氧氣和25%的葡萄糖。在哺乳動(dòng)物葡糖糖是腦組織關(guān)鍵的能量來源。神經(jīng)元獲得的葡萄糖有兩個(gè)來源：一是從血液循環(huán)中直接獲??；另外是從星形膠質(zhì)細(xì)胞獲得的[2]。

超微結(jié)構(gòu)研究顯示，腦實(shí)質(zhì)內(nèi)所有的毛細(xì)血管都被星形膠質(zhì)細(xì)胞的終足包裹，這一結(jié)構(gòu)提示星形膠質(zhì)細(xì)胞是腦攝取血液葡萄糖的最初部位。雖然在生理?xiàng)l件下腦部產(chǎn)生的能量大部分(90%～95%)被神經(jīng)元所消耗，但是約80%的腦葡萄糖利用發(fā)生于星形膠質(zhì)細(xì)胞。

與其他組織中的代謝類似，葡萄糖被葡萄糖轉(zhuǎn)運(yùn)體(glucose transporters，GLUTs)攝入腦組織細(xì)胞，在毛細(xì)血管內(nèi)皮細(xì)胞和星形膠質(zhì)細(xì)胞的終足上表達(dá)的GLUT1以及在星形膠質(zhì)細(xì)胞其他部位表達(dá)的GLUT2能夠?qū)⒀簲y帶的葡萄糖轉(zhuǎn)運(yùn)至星形膠質(zhì)細(xì)胞中[3-4]。在神經(jīng)元的細(xì)胞膜上表達(dá)有GLUT3，經(jīng)由GLUT1和GLUT2轉(zhuǎn)運(yùn)至星形膠質(zhì)細(xì)胞的葡萄糖由GLUT3轉(zhuǎn)運(yùn)至神經(jīng)元，為其能量代謝提供底物。

為了滿足其能量需求，神經(jīng)元需要保持很高的氧化代謝水平[5]。但研究發(fā)現(xiàn)，其糖酵解率與星形膠質(zhì)細(xì)胞相比水平較低。眾所周知，6-磷酸果糖激酶1是糖酵解過程中的關(guān)鍵酶，而由6-磷酸果糖激酶2催化生成的2，6-二磷酸果糖是該酶的最強(qiáng)激活劑。Herrero-Mendez A等人的研究表明，由于神經(jīng)元中存在細(xì)胞周期后期促進(jìn)復(fù)合物/周期小體(anaphase-promoting complex/cyclosome, APC/C)，而APC/C與其共激活因子Cdh1共同組成E3泛素連接酶APC/C Cdh1，這導(dǎo)致了神經(jīng)元中6-磷酸果糖激酶2的泛素化降解和低水平表達(dá)，進(jìn)而導(dǎo)致了其糖酵解水平相對(duì)較低[6]。

出現(xiàn)應(yīng)激時(shí)神經(jīng)元的這種代謝特點(diǎn)并沒有改變，其攝取的葡萄糖并不能優(yōu)先進(jìn)入糖酵解途徑，而是優(yōu)先進(jìn)入了磷酸戊糖途徑(pentose-phosphate pathway, PPP)[7]。通過PPP代謝，神經(jīng)元可以獲得還原當(dāng)量NADPH，提高谷胱甘肽的儲(chǔ)備，從而有利于神經(jīng)元的抗氧化損傷能力[8]。

顯然，神經(jīng)元的這種能量代謝特點(diǎn)與其高氧化代謝率的特點(diǎn)相矛盾，其氧化代謝的底物從何而來？實(shí)際上在大腦中生成大量的葡萄糖中間代謝產(chǎn)物來參與腦組織的能量代謝。而Pellerin L與Magistretti PJ等人發(fā)現(xiàn)，神經(jīng)元的氧化代謝更傾向于以星形膠質(zhì)細(xì)胞生成的乳酸作為底物[9-10]。

2星形膠質(zhì)細(xì)胞對(duì)神經(jīng)元乳酸利用的影響

研究發(fā)現(xiàn)，盡管星形膠質(zhì)細(xì)胞的能量消耗只占到了全腦的5%～15%，但其對(duì)葡萄糖的攝取量與其能量的消耗并不成比例[11]。實(shí)驗(yàn)研究顯示，除了可能滿足自身的能量需求外，星形膠質(zhì)細(xì)胞中的葡萄糖分解之后生成大量乳酸并釋放入細(xì)胞外[12, 13]。星形膠質(zhì)細(xì)胞具有在有氧條件下代謝葡萄糖生成乳酸的特性，稱為有氧糖酵解。因此，星形膠質(zhì)細(xì)胞在生理水平能夠生成并釋放大量的乳酸，這種作用在腦活動(dòng)增強(qiáng)時(shí)以及某些病理情況下得到加強(qiáng)[14-15]。

由于神經(jīng)元自身的糖酵解能力較低，其乳酸主要來自于星形膠質(zhì)細(xì)胞，在星形膠質(zhì)細(xì)胞與神經(jīng)元之間存在星形膠質(zhì)細(xì)胞-神經(jīng)元乳酸穿梭(astrocyte-neuron lactate shuttle，ANLS)[16]。另外，在神經(jīng)元的細(xì)胞膜上特異性的表達(dá)有單羧酸轉(zhuǎn)運(yùn)體2(monocarboxylate transporter2, MCT2)[17]。MCT2負(fù)責(zé)轉(zhuǎn)運(yùn)乳酸進(jìn)入神經(jīng)元內(nèi)及線粒體內(nèi)。神經(jīng)元內(nèi)還存在乳酸脫氫酶1(lactate dehydrogenase1, LDH1)，從而利于神經(jīng)元中乳酸的利用。由此可見，神經(jīng)元和星形膠質(zhì)細(xì)胞協(xié)同參與了腦能量代謝循環(huán)。

以上的腦部能量代謝方式稱之為ANLS假說[16](圖1)。在腦卒中時(shí)由于缺血缺氧，腦組織中有大量的乳酸生成[4]。腦缺血過程中葡萄糖通過無氧酵解的方式產(chǎn)生少量ATP；同時(shí)丙酮酸經(jīng)LDH催化還原生成乳酸。腦內(nèi)能量耗竭的刺激導(dǎo)致胞外谷氨酸濃度升高，星形膠質(zhì)細(xì)胞通過高親和力的轉(zhuǎn)運(yùn)體攝取谷氨酸，同時(shí)伴隨著Na+的內(nèi)流，兩者分別激活星形膠質(zhì)細(xì)胞內(nèi)谷氨酰胺合成酶和Na+，K+-ATP酶。Na+，K+-ATP酶的激活使ATP消耗增多，進(jìn)一步激活星形膠質(zhì)細(xì)胞內(nèi)的糖酵解相關(guān)酶，導(dǎo)致無氧糖酵解加劇，大量乳酸生成。此過程中攝取1個(gè)谷氨酸分子伴隨著3個(gè)Na+進(jìn)入細(xì)胞內(nèi)；酵解1個(gè)葡萄糖分子產(chǎn)生2分子ATP，并釋放2分子乳酸[18]。

圖1 星形膠質(zhì)細(xì)胞-神經(jīng)元乳酸穿梭假說[19]

腦缺血/缺氧后神經(jīng)元更傾向于利用乳酸而不是葡萄糖。由乳酸形成丙酮酸不需要能量，而且1分子丙酮酸可以產(chǎn)生18個(gè)分子的ATP進(jìn)入三羧酸循環(huán)，以啟動(dòng)和支持腦的有氧代謝[2]。因此，對(duì)于腦缺血患者乳酸的生成不僅僅是局部缺氧時(shí)的標(biāo)志，同時(shí)也是神經(jīng)元在缺血/缺氧狀態(tài)下能量代謝的重要代償機(jī)制。

但也有人認(rèn)為這一假說并不完全正確[20]。該觀點(diǎn)認(rèn)為，盡管ANLS假說從提出至今已有20年的歷史，但一直無法在未受損的大腦中找到乳酸穿梭存在的直接證據(jù)，且乳酸的細(xì)胞來源也不得而知。而相對(duì)于基礎(chǔ)研究，來自于臨床的學(xué)者則更看重乳酸的酸性效應(yīng)，即乳酸堆積導(dǎo)致的酸中毒可通過不同的病理生理途徑對(duì)神經(jīng)元造成損傷[21]。

基于模式研究，另外一些學(xué)者提出神經(jīng)元具有與星形膠質(zhì)細(xì)胞相比更高的葡萄糖攝取能力[22-23]。按照這種預(yù)測(cè)，神經(jīng)元主要依靠葡萄糖攝取來滿足靜息狀態(tài)和活動(dòng)狀態(tài)下的能量需求，而不是依靠從星形膠質(zhì)細(xì)胞攝取乳酸。

3星形膠質(zhì)細(xì)胞糖原對(duì)神經(jīng)元的影響

相對(duì)于機(jī)體其他部位而言，腦組織中的糖原含量比較少[22]。星形膠質(zhì)細(xì)胞是腦內(nèi)唯一具有糖原儲(chǔ)備的細(xì)胞，其從毛細(xì)血管攝取葡萄糖一部分用于有氧酵解，而多余的葡萄糖在星形膠質(zhì)細(xì)胞中以糖原的形式貯存起來。研究顯示，腦內(nèi)的糖原酵解氧化生成ATP除與谷氨酸的攝取有關(guān)外[23]，還與谷氨酸攝取后向谷氨酰胺的轉(zhuǎn)化有關(guān)[24]。星形膠質(zhì)細(xì)胞中的糖原降解酵解形成的丙酮酸要么參與谷氨酸/谷氨酰胺在細(xì)胞內(nèi)的從頭合成外[25]，要么生成乳酸，轉(zhuǎn)入神經(jīng)元被氧化分解[26]。如前所述，這為神經(jīng)元提供葡萄糖外的更多能量底物及還原當(dāng)量[27](圖2)。

圖2 星形膠質(zhì)細(xì)胞糖原對(duì)神經(jīng)元能量及神經(jīng)遞質(zhì)代謝穩(wěn)態(tài)的作用[24]

星形膠質(zhì)細(xì)胞中的糖原不僅在病理生理?xiàng)l件下作為一種能量底物，還與神經(jīng)元諸如學(xué)習(xí)行為和記憶的鞏固等功能有關(guān)。研究發(fā)現(xiàn)，感官刺激和識(shí)別記憶等認(rèn)知需求可以增加星形膠質(zhì)細(xì)胞的數(shù)量，且與該細(xì)胞內(nèi)的糖原分解有關(guān)[28]。Suh等人對(duì)大鼠在空間記憶工作的評(píng)估顯示，星形膠質(zhì)細(xì)胞糖原酵解是有選擇性地增加長(zhǎng)期而不是短期記憶[29]。腦特異性糖原合成酶基因敲除小鼠的長(zhǎng)期記憶形成受損的實(shí)驗(yàn)結(jié)果也可顯示星形膠質(zhì)細(xì)胞內(nèi)糖原對(duì)維持神經(jīng)元功能具有重要意義[30]。

4結(jié)束語(yǔ)與展望

隨著對(duì)腦組織能量代謝的深入研究，人們逐漸認(rèn)識(shí)到腦缺血時(shí)僅保護(hù)神經(jīng)元的療效并不顯著。這種情況下研究星形膠質(zhì)細(xì)胞對(duì)神經(jīng)元代謝的影響則顯得尤為重要。神經(jīng)元在不同狀態(tài)下的能量代謝是值得深入研究的課題，這對(duì)于在腦梗死等病理?xiàng)l件下如何更好地保護(hù)神經(jīng)元、最終保護(hù)腦功能具有重要的理論意義和臨床價(jià)值。

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(2015-01-26收稿)

【中圖分類號(hào)】Q954.67 R741

【文獻(xiàn)標(biāo)識(shí)碼】A

【文章編號(hào)】1007-0478(2015)06-0382-03

基金項(xiàng)目：國(guó)家自然科學(xué)基金(No81102652, 81373723, 81303053)；中國(guó)博士后科學(xué)基金資助項(xiàng)目(No2014M561959)