李蕊 胡學(xué)強(qiáng)

大量研究已經(jīng)證實(shí)雌激素具有神經(jīng)保護(hù)作用，然而長期服用雌激素可增加心血管疾病、婦科腫瘤等風(fēng)險(xiǎn)而限制了其臨床應(yīng)用，尋找中樞神經(jīng)系統(tǒng)(central nervous system，CNS)特異性靶點(diǎn)避免雌激素對(duì)其他系統(tǒng)的影響將為其治療CNS疾病提供新的思路。近年研究發(fā)現(xiàn)星形膠質(zhì)細(xì)胞在雌激素神經(jīng)保護(hù)作用中發(fā)揮重要作用?，F(xiàn)就星形膠質(zhì)細(xì)胞參與雌激素神經(jīng)保護(hù)作用的相關(guān)研究做一綜述。

1 星形膠質(zhì)細(xì)胞雌激素受體(ER)的表達(dá)

早在二十年前學(xué)者們已發(fā)現(xiàn)星形膠質(zhì)細(xì)胞是雌激素(雌二醇)在大腦中的細(xì)胞靶點(diǎn)之一。腦組織星形膠質(zhì)細(xì)胞的核和胞漿中表達(dá)ERα和ERβ，但含量比外周器官低[1]。體外培養(yǎng)的星形膠質(zhì)細(xì)胞膜上也表達(dá)ERs[2]。星形膠質(zhì)細(xì)胞參與雌激素的神經(jīng)保護(hù)作用可能主要通過細(xì)胞膜及細(xì)胞核ERα。一項(xiàng)研究發(fā)現(xiàn)星形膠質(zhì)細(xì)胞ERα基因敲除后可完全阻止ERα配體(雌激素)對(duì)實(shí)驗(yàn)性自身免疫性腦脊髓炎(experimental autoimmune encephalomyelitis, EAE)動(dòng)物模型的神經(jīng)保護(hù)作用，而神經(jīng)元ERα基因敲除則對(duì)其沒有任何影響。因此推斷星形膠質(zhì)細(xì)胞的ERα信號(hào)在細(xì)胞保護(hù)中發(fā)揮重要作用[3]。雖然ERβ也介導(dǎo)部分雌激素的神經(jīng)保護(hù)作用[4]，但ERβ基因敲除EAE中雌激素的神經(jīng)保護(hù)作用并未受影響[5]，提示ERβ并不是雌激素發(fā)揮神經(jīng)保護(hù)作用的主要受體。

2 星形膠質(zhì)細(xì)胞參與雌激素介導(dǎo)的神經(jīng)保護(hù)因子釋放

轉(zhuǎn)化生長因子α(transforming growth factor，TGFα)能夠刺激神經(jīng)細(xì)胞在受損成人大腦中增殖。2002年Galbiati等研究發(fā)現(xiàn)雌二醇上調(diào)培養(yǎng)的下丘腦1型星形膠質(zhì)細(xì)胞TGFα基因表達(dá)，推測(cè)可能與細(xì)胞核ER介導(dǎo)的機(jī)制有關(guān)。星形膠質(zhì)細(xì)胞源性TGFβ已被證實(shí)可降低缺血、缺氧、谷氨酸等引起的細(xì)胞損傷，且增多的TGFβ又能抑制星形膠質(zhì)細(xì)胞增生，減少膠質(zhì)瘢痕形成。2005年Dhandapani研究發(fā)現(xiàn)星形膠質(zhì)細(xì)胞可通過TGF-β的釋放介導(dǎo)雌二醇的神經(jīng)保護(hù)作用。在原代培養(yǎng)的嚙齒動(dòng)物膠質(zhì)細(xì)胞中，雌二醇(1～10 nmol/L)通過ER依賴的磷酸肌醇3-kinase/Akt信號(hào)通路刺激星形膠質(zhì)細(xì)胞TGFβ1和TGFβ2的表達(dá)和釋放。17β-雌二醇通過刺激星形膠質(zhì)細(xì)胞合成和釋放TGFβ1抑制β淀粉樣蛋白的神經(jīng)毒性，ER拮抗劑可阻止該作用[6]。胰島素樣生長因子1(insulin-like growth factor 1，IGF-1)對(duì)少突膠質(zhì)細(xì)胞分化、成熟、增殖及髓鞘形成十分重要，雌激素則可刺激星形膠質(zhì)細(xì)胞增生及合成IGF-1。IGF-1介導(dǎo)的少突膠質(zhì)細(xì)胞增殖需要一些激酶系統(tǒng)的激活，如P13激酶/Akt和MEK1/ERK信號(hào)通路，而17β-雌二醇可以激活星形膠質(zhì)細(xì)胞MAP激酶系統(tǒng)，進(jìn)而激活ERK[7]。堿性成纖維細(xì)胞生長因子(basic fiberoblast growth factor，bFGF)是神經(jīng)膠質(zhì)細(xì)胞和施萬細(xì)胞的促有絲分裂原，并可促進(jìn)神經(jīng)細(xì)胞的存活。雌激素在體內(nèi)外均可上調(diào)bFGF的mRNA表達(dá)[8]。

3 星形膠質(zhì)細(xì)胞參與雌激素介導(dǎo)的抗炎反應(yīng)

3.1雌激素抑制星形膠質(zhì)細(xì)胞炎性介質(zhì)的釋放雌二醇對(duì)星形膠質(zhì)細(xì)胞的抗炎作用，也有助于激素的神經(jīng)保護(hù)作用。雖然星形膠質(zhì)細(xì)胞在CNS炎性反應(yīng)形成中扮演什么角色還存在很大爭(zhēng)議，但現(xiàn)有證據(jù)顯示星形膠質(zhì)細(xì)胞可能參與免疫反應(yīng)的啟動(dòng)和調(diào)節(jié)[9]。病理狀態(tài)下，星形膠質(zhì)細(xì)胞反應(yīng)性增生，釋放大量炎性細(xì)胞因子和趨化因子吸引巨噬細(xì)胞/小膠質(zhì)細(xì)胞和T細(xì)胞/巨噬細(xì)胞到達(dá)CNS炎性反應(yīng)部位。雌二醇可在體內(nèi)外下調(diào)反應(yīng)性膠質(zhì)增生[10]，減少脂多糖(LPS)刺激培養(yǎng)的星形膠質(zhì)細(xì)胞一氧化氮和炎性反應(yīng)標(biāo)志物如腫瘤壞死因子(TNF-α)、白細(xì)胞介素6(IL-6)和干擾素誘導(dǎo)蛋白10(IFN-γ-inducible protein，IP-10)的表達(dá)[11-12]。核轉(zhuǎn)錄因子-κB (NF-κB)是許多炎性反應(yīng)基因的潛在的早期即刻轉(zhuǎn)錄調(diào)節(jié)因子，雌激素則可減少LPS誘導(dǎo)的NF-κB激活[10, 12-13]。

3.2雌激素促進(jìn)星形膠質(zhì)細(xì)胞對(duì)谷氨酸的再攝取在CNS中，星形膠質(zhì)細(xì)胞通過L-谷氨酸-天門冬氨酸轉(zhuǎn)運(yùn)體(L-glutamate/L-aspartate trans-porter，GLAST)和谷氨酸轉(zhuǎn)運(yùn)體(glutamate transporter-1，GLT-1)對(duì)細(xì)胞間隙的谷氨酸進(jìn)行攝取，維持胞外正常的興奮性神經(jīng)遞質(zhì)濃度。持續(xù)高濃度的谷氨酸環(huán)境可促使小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞NF-κB激活，誘導(dǎo)致炎基因合成使炎性反應(yīng)擴(kuò)大，這是許多神經(jīng)系統(tǒng)炎性疾病及神經(jīng)退行性疾病的病理機(jī)制之一[14]。Liang等研究表明雌激素可增加阿爾茨海默病患者中星形膠質(zhì)細(xì)胞對(duì)谷氨酸的攝取而發(fā)揮神經(jīng)保護(hù)作用。Pawlak等進(jìn)一步研究發(fā)現(xiàn)高濃度雌激素(10～100 nmol/L)增加GLAST和GLT-1的表達(dá)從而增加對(duì)谷氨酸再攝取作用，防止持續(xù)的神經(jīng)元興奮性毒性損傷及CNS炎性反應(yīng)的擴(kuò)大。

3.3雌激素影響星形膠質(zhì)細(xì)胞與淋巴細(xì)胞的相互作用雌激素亦影響星形膠質(zhì)細(xì)胞與淋巴細(xì)胞的信號(hào)傳遞。早在1996年Gold等就已經(jīng)報(bào)道星形膠質(zhì)細(xì)胞可誘導(dǎo)致腦炎T細(xì)胞凋亡，而17β雌二醇可特異性增強(qiáng)這種效果。此外，雌激素阻止星形膠質(zhì)細(xì)胞表面主要組織相容性復(fù)合物Ⅱ類分子(major histocompatibility complex Ⅱ，MHC Ⅱ)的表達(dá)從而選擇性抑制星形膠質(zhì)細(xì)胞與淋巴細(xì)胞的交互作用。雌激素的這種作用機(jī)制并不受MHCⅡ類分子轉(zhuǎn)錄激活因子mRNA或蛋白水平的影響，而與MHCⅡ類分子啟動(dòng)子的組蛋白乙?；癄顟B(tài)改變有關(guān)[15]。

4 不同神經(jīng)組織及病理狀態(tài)下星形膠質(zhì)細(xì)胞對(duì)雌激素反應(yīng)的差異

不同區(qū)域神經(jīng)組織的星形膠質(zhì)細(xì)胞在病理狀態(tài)下可能通過不同途徑參與雌激素的神經(jīng)保護(hù)作用。雌激素下調(diào)大鼠海馬中老化相關(guān)星形膠質(zhì)細(xì)胞[16]。此外，雌二醇降低大腦皮質(zhì)和海馬腦損傷后膠質(zhì)細(xì)胞增殖[17]，這與雌激素處理后的原代培養(yǎng)的星形膠質(zhì)細(xì)胞增殖減少、死亡增加的發(fā)現(xiàn)一致[18]。這些研究表明至少在灰質(zhì)，雌二醇有助于減少神經(jīng)退行性變狀態(tài)下膠質(zhì)反應(yīng)。而與之相反的是，雌二醇增加cuprizone誘導(dǎo)的脫髓鞘模型中白質(zhì)星形膠質(zhì)細(xì)胞增殖[7, 19]。雌激素也增加脊髓機(jī)械損傷后星形膠質(zhì)細(xì)胞表面標(biāo)志物膠質(zhì)纖維酸性蛋白(glial fibrillary acidic protein, GFAP)和反應(yīng)性星形膠質(zhì)細(xì)胞數(shù)量[20]，以及興奮性損傷后嗅球GFAP表達(dá)[21]。有學(xué)者推測(cè)雌二醇對(duì)灰白質(zhì)星形膠質(zhì)細(xì)胞的作用可能不同，脊髓大部分由白質(zhì)組成可能是雌二醇對(duì)該處星形膠質(zhì)細(xì)胞的調(diào)節(jié)作用不同于海馬及腦皮質(zhì)星形膠質(zhì)細(xì)胞的原因。此外，星形膠質(zhì)細(xì)胞對(duì)激素不同的反應(yīng)可能與CNS雌激素受體的區(qū)域表達(dá)差異有關(guān)。雖然星形膠質(zhì)細(xì)胞的功能在不同區(qū)域及病理狀態(tài)下可能不同，但對(duì)雌二醇介導(dǎo)神經(jīng)保護(hù)似乎均有益。如在一些情況下雌二醇減少星形膠質(zhì)細(xì)胞數(shù)量及其促炎因子的表達(dá)[11-12, 22]，而在另外一些情況下雌二醇增加星形膠質(zhì)細(xì)胞的數(shù)量及其分泌神經(jīng)保護(hù)因子，促進(jìn)神經(jīng)細(xì)胞存活及再生[6-7, 10]。

5 星形膠質(zhì)細(xì)胞參與雌激素介導(dǎo)的其他神經(jīng)保護(hù)作用

除了經(jīng)典的雌激素受體激活途徑，雌激素還可通過非經(jīng)典受體激活途徑介導(dǎo)神經(jīng)保護(hù)。激活星形膠質(zhì)細(xì)胞上的TrkA受體可調(diào)節(jié)軸突生長和突觸可塑性[23]。線粒體呼吸鏈功能障礙多伴隨神經(jīng)系統(tǒng)退行性變。雌激素作用于星形膠質(zhì)細(xì)胞調(diào)節(jié)線粒體呼吸鏈活性，上調(diào)線粒體呼吸鏈復(fù)合物亞基的基因表達(dá)及線粒體DNA含量。該過程是否依賴細(xì)胞核及線粒體ER受體研究結(jié)果不一致[24-26]。另外，雌二醇通過增加腦實(shí)質(zhì)反應(yīng)性星形膠質(zhì)細(xì)胞和血管周圍膠質(zhì)細(xì)胞足突上水通道蛋白4表達(dá)抑制腦水腫[27]。

綜上所述，星形膠質(zhì)細(xì)胞在雌激素神經(jīng)保護(hù)作用中發(fā)揮重要作用，且主要依賴于星形膠質(zhì)細(xì)胞膜ERs和核ERs。如何特異性激活星形膠質(zhì)細(xì)胞上的ER發(fā)揮類雌激素的神經(jīng)保護(hù)作用，而避免雌激素的其他不良反應(yīng)需要進(jìn)一步研究。選擇性雌激素受體調(diào)節(jié)劑(selective estrogen receptor modulators，SERMs)已為人類帶來了希望[5]。雷洛昔芬作為SERMs的代表，因其對(duì)骨組織有雌激素作用(ER激動(dòng)劑作用)，而對(duì)乳腺和子宮具有抗雌激素作用(ER拮抗劑作用)，已經(jīng)成功地作為絕經(jīng)后婦女骨質(zhì)疏松的預(yù)防藥物。這將使臨床應(yīng)用SERMs特異性激活星形膠質(zhì)細(xì)胞ER發(fā)揮雌激素樣神經(jīng)保護(hù)作用成為可能。體外實(shí)驗(yàn)已證實(shí)他莫昔芬、雷洛昔芬、ospemifene和bazedoxifene 4種SERMs可作用于星形膠質(zhì)細(xì)胞的ER發(fā)揮神經(jīng)保護(hù)作用。 這4種SERMs均可降低LPS處理的星形膠質(zhì)細(xì)胞IL-6和IP-10表達(dá)[12]。此外他莫昔芬降低星形膠質(zhì)細(xì)胞轉(zhuǎn)運(yùn)L-谷氨酸，該過程涉及PI3K和MAPK信號(hào)轉(zhuǎn)導(dǎo)通路[28]。雷洛昔芬可減少老年動(dòng)物大腦中星形膠質(zhì)細(xì)胞的數(shù)量[1]。ospemifene和bazedoxifene可能通過轉(zhuǎn)錄因子P65(NF-κB家族成員)基因轉(zhuǎn)位阻斷其轉(zhuǎn)錄活性抑制星形膠質(zhì)細(xì)胞NF-κB誘導(dǎo)的促炎趨化因子和細(xì)胞因子轉(zhuǎn)錄[12]。進(jìn)一步探尋星形膠質(zhì)細(xì)胞與雌激素之間的相互作用有助于更好地指導(dǎo)其臨床應(yīng)用。

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