陳四化 劉吉星 任海軍
(蘭州大學(xué)第二醫(yī)院神經(jīng)外科,甘肅 蘭州 730000)
·綜述·
神經(jīng)遞質(zhì)對神經(jīng)干細胞增殖的調(diào)控
陳四化 劉吉星 任海軍*
(蘭州大學(xué)第二醫(yī)院神經(jīng)外科,甘肅 蘭州 730000)
神經(jīng)遞質(zhì); 神經(jīng)干細胞; 增殖; 調(diào)控
在過去的幾年中,許多研究報道了在成人中樞神經(jīng)系統(tǒng)中神經(jīng)干細胞(neural stem cells,NSCs)能夠分化成新的神經(jīng)元,即星形膠質(zhì)細胞和少突膠質(zhì)細胞。這一發(fā)現(xiàn)推翻了在出生后中樞神經(jīng)系統(tǒng)不能再生的中心假設(shè),同時也為理解神經(jīng)分化的分子原理基礎(chǔ)以及神經(jīng)組織修復(fù)新療法的開發(fā)奠定了基礎(chǔ)[1]。NSCs的增殖分化受細胞外環(huán)境信號和細胞內(nèi)基因有序表達的雙重控制。神經(jīng)遞質(zhì)作為細胞外環(huán)境信號中一員的,不僅介導(dǎo)神經(jīng)元之間、神經(jīng)元和效應(yīng)器之間的信息傳遞,還在調(diào)節(jié)成人神經(jīng)干細胞的增殖,分化和突觸融合,以及成人神經(jīng)發(fā)生中發(fā)揮重要作用[2]。本文旨對幾種重要的神經(jīng)遞質(zhì)對位于哺乳動物大腦腦室下區(qū)(subventricular zone,SVZ)和顆粒下層(subgranular zone,SGZ)的前體細胞增殖的調(diào)控作一綜述。
1.多巴胺(dopamine,DA):DA是兒茶酚胺類物質(zhì),由黑質(zhì)腹側(cè)被蓋區(qū)和下丘腦的神經(jīng)元合成。DA受體為G蛋白偶聯(lián)受體,分為D1樣和D2樣。D1樣受體激活腺苷酸環(huán)化酶,D2樣受體抑制腺苷酸環(huán)化酶。D1樣受體存在于細胞質(zhì)中而不是存在于短暫擴增細胞和成纖維細胞膜上,D2樣受體主要在短暫擴增細胞膜上表達,少量在SVZ星形膠質(zhì)細胞膜上表達。短暫擴增細胞表達D3受體而神經(jīng)母細胞和SVZ的膠質(zhì)細胞卻不表達D3受體[3]。嚙齒類動物中,通過注射的選擇性神經(jīng)毒素,如6-羥基多巴胺或1-甲基4-苯基-1,2,3,6-四氫吡啶消融中腦多巴胺神經(jīng)元,可以減少SVZ前體細胞的增殖和神經(jīng)發(fā)生[4]。然而,在另一研究中,DA受體拮抗劑氟哌啶醇給藥14 d導(dǎo)致SVZ神經(jīng)前體細胞數(shù)目的增加[5]。對于上述不同研究結(jié)果表明同樣的神經(jīng)遞質(zhì)可能對NSCs的增殖發(fā)揮相反的作用。這一作用可能是DA不同受體亞型的激活所介導(dǎo)。長期激活DA受體可能會抑制NSCs的增殖,然而短期內(nèi)激活DA受體促進NSCs的增殖。DA受體介導(dǎo)的調(diào)控NSCs增殖依賴于睫狀神經(jīng)營養(yǎng)因子,而已知睫狀神經(jīng)營養(yǎng)因子能夠促進SVZ神經(jīng)干細胞的增殖[6]。最近的一項研究提出,激活的DA受體主要通過Akt和細胞外信號調(diào)節(jié)激酶1/2(extracellular signal-regulated kinase,ERK1/2)信號促進NSCs增殖[7]。而其它的研究表明,激活的DA受體可以刺激表皮生長因分泌從而促進NSCs增殖[7]。
2.谷氨酸(glutamic acid,GAA):在中樞神經(jīng)系統(tǒng)中,GAA是一種興奮性神經(jīng)遞質(zhì),它有幾種不同的受體亞型:即離子型的N-甲基-D-天門冬氨(N-methyl-D-aspartate,NMDA)受體、(2-氨基-3-3-羥基-5-甲基-異惡唑-哌啶-4-基)丙酸[2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid],AMPA受體、紅藻氨酸 (kamate,KA) 受體以及代謝型谷氨酸受體(metabotropic glutamate receptor,mGluR)[8]。電生理和免疫組化研究顯示各種谷氨酸受體在成年側(cè)腦室的SVZ和齒狀回SGZ的神經(jīng)前體細胞中均有表達[9]。GAA無論作用于代謝型或離子型受體都為神經(jīng)前體細胞的動員提供了重要信號[8]。已經(jīng)檢測到代謝型谷氨酸受體mGluR3、mGluR4和mGluR5在成年海馬神經(jīng)祖細胞上表達和mGluR5在放射狀膠質(zhì)細胞樣細胞上表達[9]。生理條件下,NMDA受體激動劑抑制表達mGluR5的放射狀膠質(zhì)細胞樣細胞增殖[9]。而在腦損傷條件下,NMDA受體激動劑促進放射狀膠質(zhì)細胞樣細胞增殖[10]。NMDA受體通過抑制神經(jīng)膠質(zhì)細胞上游堿性環(huán)-螺旋-(basic-helix-loop-helix,bHLH)的Hes1基因和DNA結(jié)合抑制因子2(inhibitor of DNA binding 2,Id2 )的表達和促進轉(zhuǎn)錄因子神經(jīng)源性分化(neurogenic differentiation,NeuroD)的表達誘導(dǎo)成年海馬祖細胞的增殖[10]。
在SVZ,體內(nèi)的放射狀膠質(zhì)細胞樣細胞或在短暫擴充細胞上都尚未發(fā)現(xiàn)谷氨酸受體表達。Platel等已證實代謝型谷氨酸受體和KA受體在SVZ的神經(jīng)母細胞上表達[10]。在體外,谷氨酸促進來源于SVZ神經(jīng)祖細胞的增殖[5]。在體內(nèi)敲除NMDA受體基因?qū)е律窠?jīng)母細胞凋亡,表明NMDA受體對神經(jīng)母細胞的存活至關(guān)重要[10]。紅藻氨酸受體GLUK5在腦室下區(qū)神經(jīng)母細胞的遷移過程中被完全激活,而這種激活降低神經(jīng)母細胞遷移速度[8]。眾所周知谷氨酸鹽信號通過介導(dǎo)神經(jīng)營養(yǎng)因子,如腦源性神經(jīng)營養(yǎng)因子,神經(jīng)生長因子和成纖維細胞生長因子的分泌促進神經(jīng)干細胞增殖[2]。在成人大腦GAA介導(dǎo)祖細胞增殖調(diào)控的下游機制還沒有被廣泛研究。
3.γ-氨基丁酸(γ-aminobutyric acid,GABA):GABA在成年脊椎動物大腦內(nèi)是主要的抑制性神經(jīng)遞質(zhì),它通過激活離子型配體門控GABAA、GABAB或GABAC受體和G蛋白偶聯(lián)受體發(fā)揮作用。研究發(fā)現(xiàn),成年小鼠海馬神經(jīng)干細胞及其后代表達GABAB受體[11]。GABAB受體的藥物抑制刺激NSCs增殖和在體內(nèi)GABAB1受體亞基基因的缺失促進NSCs增殖和神經(jīng)母細胞的分化[11]。Song等結(jié)合光遺傳學(xué)和克隆譜系跟蹤技術(shù)研究發(fā)現(xiàn)在齒狀回的GABA由表達小清蛋白的中間神經(jīng)元釋放和通過激活含γ2亞基-GABAA受體抑制靜態(tài)放射狀膠質(zhì)細胞樣細胞的活化[12]。
在成年SVZ,GABA由神經(jīng)母細胞以鈣依賴性非囊泡形式合成釋放,通過GABAA受體激活去極化神經(jīng)母細胞并抑制神經(jīng)母細胞增殖[13]。在成年SVZ激活GABAA受體誘導(dǎo)組蛋白H2AX的磷酸化,抑制細胞周期中DNA的合成,進而發(fā)揮GABA對該區(qū)域的細胞周期的抑制效果[13]。Alfonso等[14]研究發(fā)現(xiàn),在SVZ神經(jīng)母細胞表達能夠結(jié)合地西泮結(jié)合抑制劑的GABAA受體亞單位,抵消GABA釋放對神經(jīng)神經(jīng)干細胞的抑制作用。
4.5-羥色胺 (5-hydroxytryptamine,5-HT):5-HT是SVZ的中縫核神經(jīng)元合成的單胺類物質(zhì)[5]。在腦室下區(qū)5-HT受體的表達模式仍存在爭議。Councill[15]等提出從SVZ組織的逆轉(zhuǎn)錄聚合酶鏈反應(yīng)表明5-HT受體,如5-HT1A,5-HT1B,5-HT1D,5-HT2A,5-HT2B,5-HT2C,5-HT3A和5-HT6在SVZ神經(jīng)元上廣泛表達,但是只有受體5-HT1A,5-HT2A和5-HT2C在腦室下區(qū)神經(jīng)元上表達文獻已報到。普遍認為5-HT 對腦室下區(qū)神經(jīng)發(fā)生產(chǎn)生積極影響,因為在體內(nèi)注射5-HT會促進腦室下區(qū)神經(jīng)球產(chǎn)生.Tegenge等[16]通過特異性受體激動劑急性或慢性激活5-HT受體5-HT1A和5-HT2發(fā)現(xiàn)腦室下區(qū)和嗅球5-溴脫氧尿嘧啶核苷(5-bromo-2-deoxyuridine,BrdU)標(biāo)記的神經(jīng)干細胞數(shù)量增多,而對神經(jīng)膠質(zhì)細胞和新生神經(jīng)元的比例沒有影響。然而,慢性激活5HT1A可能阻止新生神經(jīng)元向嗅球的遷移。
5.一氧化氮(nitric oxide,NO):NO是一種非典型性神經(jīng)遞質(zhì),它不被存儲在囊泡或通過胞吐作用釋放出來,而是在合成位置釋放,并通過擴散穿透細胞膜進入鄰近的細胞。在大腦中, NO是由三種不同的一氧化氮合酶 (nitric oxide synthases,NOSs),神經(jīng)元一氧化氮合酶(neuronal NOS,nNOS)內(nèi)皮一氧化氮合酶(endothelial NOS,eNOS)和誘導(dǎo)型一氧化氮合酶(inducible NOS,iNOS)合成。nNOS是由靠近腦室下區(qū)和齒狀回的神經(jīng)元表達。在生理條件下, NO抑制神經(jīng)干細胞增殖,而在腦損傷條件下NO促進神經(jīng)干細胞增殖[5]。在生理條件下,2個月小鼠腦室下區(qū)和齒狀回中缺乏功能性的nNOS促進神經(jīng)干細胞增殖[17]。體外研究表明 NO通過作用于表皮生長因子受體抑制神經(jīng)干細胞增殖[18]。Carreira等[19〗研究表明,在腦損傷條件下NO能先后激活兩條獨立的信號途徑細胞外信號調(diào)控激酶(extracellular signal -regulated kinase,EPK)/絲裂原活化蛋白激酶(mitogen-activated protein,MAPK)和鳥苷酸環(huán)化酶(guanylate cyclase,GC)/環(huán)磷酸鳥苷(cyclic guanosine monophosphate,cGMP)/cGMP依賴蛋白激酶G(cGMP-dependent protein kinase G,PKG)促進神經(jīng)干細胞增殖。
6.乙酰膽堿(acetylcholine,Ach):輸入到齒狀回的膽堿能來自內(nèi)側(cè)隔核。用離子型乙酰膽堿受體激動劑煙堿長期治療已經(jīng)顯示在齒狀回減少增殖[20]。在成人大腦膽堿能神經(jīng)元的消融導(dǎo)致顆粒下層區(qū)神經(jīng)干細胞增殖的減少,同時也損害空間記憶[21]。膽堿能藥物對SVZ和SGZ神經(jīng)干細胞增殖發(fā)揮不同的調(diào)節(jié)作用[22]。在顆粒下層區(qū)的放射狀膠質(zhì)細胞樣細胞和聚唾液酸-神經(jīng)細胞黏附分子陽性細胞上毒蕈堿型乙酰膽堿受體表達已經(jīng)被確定[23]。給予乙酰膽堿藥10 d通過激活毒蕈堿M1受體促進顆粒下層區(qū)神經(jīng)干細胞增殖,而通過激活煙堿受體發(fā)揮相反的作用。在嚙齒類動物,功能性a4b2煙堿型膽堿能受體(nicotinic acetylcholine receptors,nAChR)通過促進Math1基因的表達,決定神經(jīng)干細胞增殖和分化[23]。
神經(jīng)干細胞移植治療腦中風(fēng)已成為當(dāng)研究的熱點。移植后的神經(jīng)干細胞在一定條件下能夠分化成具有形態(tài)學(xué)和電生理特性的神經(jīng)元。神經(jīng)遞質(zhì)作為細胞外環(huán)境的一員參與調(diào)控神經(jīng)干細胞在體內(nèi)外的增殖和分化。深入研究神經(jīng)遞質(zhì)對腦室下區(qū)和顆粒下層區(qū)神經(jīng)干細胞增殖調(diào)控機制,為研究神經(jīng)遞質(zhì)和神經(jīng)遞質(zhì)受體藥理機制奠定了基礎(chǔ)。
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1671-2897(2016)15-558-03
國家自然科學(xué)基金資助項目(C030307)
陳四化,碩士,E-mail:354409914@qq.com
*通訊作者:任海軍,主任醫(yī)師,E-mail:baiyunguan@hotmail.com
R 651
A
2014-09-02;
2015-01-30)