韓國(guó)英，李春燕(綜述)，時(shí)海波，殷善開(審校)

(上海交通大學(xué)附屬第六人民醫(yī)院耳鼻咽喉科，上海 200233)

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利魯唑的神經(jīng)保護(hù)作用及其機(jī)制的研究進(jìn)展

韓國(guó)英△，李春燕※(綜述)，時(shí)海波，殷善開(審校)

(上海交通大學(xué)附屬第六人民醫(yī)院耳鼻咽喉科，上海 200233)

摘要：利魯唑(2-氨基-6-三氟甲氧基-苯并噻唑)屬苯并噻唑類化合物，具有明確的神經(jīng)保護(hù)藥理作用。它的主要作用是抑制多種受體和離子通道介導(dǎo)的谷氨酸突觸傳導(dǎo)和神經(jīng)元超興奮性，提高神經(jīng)營(yíng)養(yǎng)因子的表達(dá)量，保護(hù)神經(jīng)元免受興奮毒性損傷，促進(jìn)神經(jīng)元的存活。該文就利魯唑神經(jīng)保護(hù)作用及其機(jī)制的相關(guān)研究進(jìn)展進(jìn)行綜述。

關(guān)鍵詞：利魯唑；神經(jīng)保護(hù)；谷氨酸

利魯唑?qū)俦讲⑧邕蝾惢衔铮?995年起作為處方藥用于肌萎縮性脊髓側(cè)索硬化的臨床治療，而對(duì)其他的中樞神經(jīng)系統(tǒng)疾病(如焦慮、抑郁及驚厥等)的臨床前實(shí)驗(yàn)治療效果也得到了廣泛的關(guān)注和認(rèn)可[1-2]。谷氨酸引起的興奮毒性是這些中樞神經(jīng)系統(tǒng)疾病的共同分子機(jī)制，其顯著的抗谷氨酸毒性的能力是利魯唑神經(jīng)保護(hù)作用的主要機(jī)制之一?，F(xiàn)對(duì)利魯唑的神經(jīng)保護(hù)作用及其機(jī)制綜述如下。

1利魯唑的神經(jīng)元保護(hù)作用

大量的體外(突觸體和腦片)和體內(nèi)實(shí)驗(yàn)均證實(shí)利魯唑?qū)ι窠?jīng)元損傷具有較強(qiáng)的保護(hù)作用。丙二酸二乙酯能抑制線粒體能量的產(chǎn)生及神經(jīng)膠質(zhì)細(xì)胞對(duì)谷氨酸的重?cái)z取，利用它慢性處理新生大鼠腦皮質(zhì)腦片，能造成大量大錐體神經(jīng)元死亡，而利魯唑(10 μmol/L)能顯著抑制丙二酸二乙酯的毒性作用[3]。Nogradi等[4]發(fā)現(xiàn)，成年大鼠脊髓腹根撕脫傷在腹根再植術(shù)治療后仍有大量運(yùn)動(dòng)神經(jīng)元死亡。而繼腹根再植后聯(lián)合應(yīng)用利魯唑治療對(duì)運(yùn)動(dòng)神經(jīng)元有良好的保護(hù)作用，并促進(jìn)軸突再生進(jìn)入撕脫的腹根。Wang等[5]發(fā)現(xiàn)，耳蝸內(nèi)或腹腔注射利魯唑能保護(hù)豚鼠耳蝸毛細(xì)胞免受噪聲損傷誘導(dǎo)的細(xì)胞調(diào)亡，其半數(shù)有效量為17 μmol/L。在臨床研究中利魯唑?qū)∥s性脊髓側(cè)索硬化[6]、帕金森病[7]等神經(jīng)退行性疾病有明顯的治療作用，而其對(duì)抗抑郁和焦慮等精神疾病的研究也取得了可喜的進(jìn)展[8]。在鋰治療中度躁狂抑郁癥的前瞻性試驗(yàn)中14例患者治療效果不明顯，而聯(lián)合服用鋰和利魯唑(171 mg/d)8周后抑郁癥狀得到顯著改善[1]。Sanacora等[2]也發(fā)現(xiàn)，利魯唑(95 mg/d)聯(lián)合抗抑郁藥物治療6～12周后，難治性抑郁癥患者的抑郁癥狀明顯改善。

2利魯唑神經(jīng)保護(hù)機(jī)制

2.1利魯唑抑制神經(jīng)元超興奮及興奮毒性

2.1.1利魯唑抑制谷氨酸能突觸傳遞在谷氨酸突觸傳遞過程中，突觸前神經(jīng)元由前膜電壓依賴性鈉通道開放引發(fā)去極化，繼而前膜電壓依賴性鈣通道開放，鈣離子內(nèi)流并引發(fā)突觸小泡內(nèi)谷氨酸釋放至突觸間隙。谷氨酸與突觸后受體結(jié)合，受體開放，介導(dǎo)鈉離子、鈣離子和鉀離子(尤其是鈉離子)內(nèi)流，突觸后膜產(chǎn)生去極化，誘發(fā)突觸后神經(jīng)元發(fā)放動(dòng)作電位。既往研究證實(shí)，利魯唑能從突觸前、突觸間隙及突觸后受體三個(gè)方面拮抗谷氨酸興奮毒性。

2.1.1.1觸前機(jī)制大量研究證實(shí)，利魯唑能顯著抑制多種生物體中樞神經(jīng)系統(tǒng)突觸前谷氨酸釋放[9-10]。在大鼠慢性坐骨神經(jīng)痛模型實(shí)驗(yàn)中[11]，腹腔注射利魯唑(6～12 mg/kg)能顯著減少福爾馬林誘導(dǎo)的脊髓背角神經(jīng)元谷氨酸的釋放。

鈣離子是突觸釋放過程中的關(guān)鍵因素，因此鈣離子通道及突觸前鈣離子濃度的變化將影響正常的突觸活性。利魯唑可通過阻斷突觸前電壓門控性鈣通道，從而減少鈣離子內(nèi)流及細(xì)胞內(nèi)鈣離子濃度，抑制神經(jīng)元的突觸活性。Stefani等[12]報(bào)道，利魯唑能抑制新生及成熟大鼠皮質(zhì)神經(jīng)元高電壓(high voltage activated,HVA)激活和低電壓激活鈣電流。其最大抑制幅度分別為20%和12%。在IMR32神經(jīng)母細(xì)胞瘤細(xì)胞和培養(yǎng)的胚胎大鼠運(yùn)動(dòng)神經(jīng)元中，利魯唑(100 ～1000 μmol/L)通過阻斷L型HVA鈣離子通道和細(xì)胞內(nèi)儲(chǔ)存鈣的釋放減少細(xì)胞內(nèi)鈣濃度[13]。此外，ω-agatoxin-IVA(蜘蛛毒提取物)，P/Q型HVA鈣離子通道的特異性拮抗劑，可阻斷利魯唑(1 μmol/L)對(duì)大鼠大腦皮質(zhì)突觸體谷氨酸釋放的抑制作用[10]。這些研究提示，阻斷P/Q型HVA和低電壓激活鈣離子通道可能是利魯唑抑制突觸前谷氨酸釋放的重要機(jī)制。

此外，據(jù)研究蛋白激酶C激活能上調(diào)N-甲基-D-天冬胺酸(N-methyl-D-aspartate，NMDA)受體的表達(dá)和功能[14-15]。利魯唑已被研究證實(shí)能直接抑制蛋白激酶C的活性，從而抑制突觸前膜NMDA受體對(duì)遞質(zhì)釋放的易化作用，減少谷氨酸的釋放[16-17]。

2.1.1.2利魯唑增加突觸間隙谷氨酸的重?cái)z取神經(jīng)末梢釋放至突觸間隙的谷氨酸可被位于神經(jīng)末梢和神經(jīng)膠質(zhì)細(xì)胞膜上的高親和力谷氨酸轉(zhuǎn)運(yùn)體重?cái)z取，以終止其突觸傳遞效應(yīng)。Fumagalli等[18]發(fā)現(xiàn)，利魯唑(0.01～100 μmol/L)能有效增加穩(wěn)定表達(dá)于人胚腎細(xì)胞293的三大谷氨酸轉(zhuǎn)運(yùn)體的活性：谷氨酸/天冬氨酸轉(zhuǎn)運(yùn)體、興奮性氨酸轉(zhuǎn)運(yùn)體1和谷氨酸轉(zhuǎn)運(yùn)體1，并且這種效應(yīng)具有劑量依賴性，在大鼠實(shí)驗(yàn)中觀察到利魯唑(0.1～1 μmol/L)能增加脊髓突觸體谷氨酸的重?cái)z取[19]。而在之后的一項(xiàng)研究表明[20]，在野生型和G93A SOD1轉(zhuǎn)基因大鼠中，更高濃度的利魯唑(10～300 μmol/L)才有此效應(yīng)。此外，近期研究發(fā)現(xiàn)[21]，利魯唑能上調(diào)突觸間隙中負(fù)責(zé)清除谷氨酸的星形細(xì)胞谷氨酸轉(zhuǎn)運(yùn)體數(shù)量和活性。利魯唑通過增加谷氨酸轉(zhuǎn)運(yùn)體攝取，加快突觸間隙對(duì)谷氨酸的除，從而使突觸后膜受體激活減少，繼之抑制谷氨酸突觸傳遞功能。

2.1.1.3利魯唑?qū)ν挥|后受體的直接影響應(yīng)用放射性配體結(jié)合技術(shù)的研究證明[22-23]，利魯唑(100 μmol/L)與NMDA、非NMDA谷氨酸受體和代謝型谷氨酸受體的NMDA沒有結(jié)合位點(diǎn)。Sankaranarayanan等[24]發(fā)現(xiàn)，利魯唑(100 μmol/L)能抑制放射性配體與NMDA或代謝型谷氨酸受體的NMDA位點(diǎn)的結(jié)合，但作用并不顯著。這些研究表明，利魯唑與谷氨酸受體無結(jié)合位點(diǎn)，同時(shí)對(duì)于谷氨酸與其受體的結(jié)合有直接抑制作用但作用有限。此外，有研究觀察到[25]，利魯唑(10 μmol/L)不影響脊髓神經(jīng)元中自發(fā)的興奮性突觸后電流和外源性谷氨酸激活的突觸后電流的幅度，提示其不改變突觸后谷氨酸受體的敏感性。然而，有研究證實(shí)[26]，20和30 μmol/L 利魯唑能分別減小舌下運(yùn)動(dòng)神經(jīng)元和紋狀體棘狀神經(jīng)元外源性谷氨酸激活的谷氨酸受體電流的幅度。這些研究結(jié)果不一致的原因可能與其藥物濃度和神經(jīng)元種類等的差異有關(guān)。

2.1.2利魯唑?qū)ι窠?jīng)元興奮性調(diào)節(jié)的其他通路

2.1.2.1利魯唑抑制持續(xù)性鈉電流在多種神經(jīng)元中已證實(shí)[25,27-28]，利魯唑能顯著減少神經(jīng)元的持續(xù)放電而并不改變其靜息膜性能，如靜息膜電位或輸入電阻。低濃度利魯唑(0.1～1 μmol/L)能增加神經(jīng)元放電閾值，穩(wěn)定非開放狀態(tài)的電壓依賴性鈉通道，而較高濃度利魯唑(2～10 μmol/L)可完全阻斷神經(jīng)元?jiǎng)幼麟娢坏陌l(fā)放。與此同時(shí)，大量研究報(bào)道低濃度(<10 μmol/L)利魯唑即可顯著抑制神經(jīng)元的持續(xù)性鈉電流，并且利魯唑?qū)Τ掷m(xù)性鈉電流的抑制作用與其對(duì)神經(jīng)元持續(xù)性放電的作用具有相似的劑量關(guān)系，提示利魯唑主要通過抑制持續(xù)性鈉電流來減少神經(jīng)元的連續(xù)放電，降低神經(jīng)元興奮性[29-31]。

2.1.2.2利魯唑抑制鈣依賴性鉀通道鈣依賴性鉀通道受電壓和鈣離子的雙重調(diào)控，通道開放可增加動(dòng)作電位之后的后超極化幅度和時(shí)程。有研究報(bào)道[32]，利魯唑能增加鈣依賴性鉀通道開放概率,加大神經(jīng)元后超極化,抑制其緊張式自發(fā)放電的產(chǎn)生和頻率，從而降低神經(jīng)元興奮性。

2.1.2.3利魯唑增強(qiáng)突觸后氨基丁酸受體的反應(yīng)性早期的研究顯示，利魯唑(100 μmol/L)對(duì)突觸后GABAA，GABAB或甘氨酸受體并無高親和力，且利魯唑并沒有競(jìng)爭(zhēng)這些受體的放射性配體結(jié)合位點(diǎn)。隨后有研究則發(fā)現(xiàn)[33-34]，利魯唑(30～300 μmol/L)增加海馬神經(jīng)元和人胚腎細(xì)胞293細(xì)胞中外源性GABA誘導(dǎo)的抑制性突觸后電流幅度，并具有劑量依賴性。提示利魯唑可增強(qiáng)GABA受體的敏感性，加強(qiáng)突觸后GABA抑制作用,降低神經(jīng)元興奮能力。

2.2利魯唑提高神經(jīng)營(yíng)養(yǎng)因子的表達(dá)量神經(jīng)生長(zhǎng)因子、膠質(zhì)細(xì)胞源性神經(jīng)營(yíng)養(yǎng)因子和腦源性神經(jīng)營(yíng)養(yǎng)因子均屬于神經(jīng)營(yíng)養(yǎng)因子家族，是一類由神經(jīng)所支配的組織和星形膠質(zhì)細(xì)胞產(chǎn)生的，具有促進(jìn)神經(jīng)元的發(fā)育、分化、生長(zhǎng)和存活作用的蛋白質(zhì)。Mizuta等[35]發(fā)現(xiàn)，在培養(yǎng)的小鼠星形膠質(zhì)細(xì)胞中，利魯唑(100 μmol/L)能上調(diào)這三類營(yíng)養(yǎng)因子的信使RNA表達(dá)水平。

Caumont等[36]研究發(fā)現(xiàn)，在培養(yǎng)的大鼠神經(jīng)膠質(zhì)瘤細(xì)胞中，通過調(diào)節(jié)促絲裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)信號(hào)通路上細(xì)胞外相關(guān)激酶的轉(zhuǎn)錄，利魯唑(1 μmol/L)能上調(diào)膠質(zhì)細(xì)胞源性神經(jīng)營(yíng)養(yǎng)因子信使RNA和蛋白表達(dá)水平。腹腔注射利魯唑(19 mg/kg)引起成年小鼠齒狀回神經(jīng)元和海馬CA3區(qū)的腦源性神經(jīng)營(yíng)養(yǎng)因子表達(dá)量增加，這種效應(yīng)是通過N型鈣通道和腺苷A1受體介導(dǎo)的p38MAPK的活化來完成的[37]。這些實(shí)驗(yàn)證實(shí)在體和離體條件下利魯唑(1～100 μmol/L)均能增加神經(jīng)營(yíng)養(yǎng)因子的表達(dá)量，促進(jìn)神經(jīng)元的存活。神經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞MAPK信號(hào)通路在利魯唑的作用機(jī)制中具有重要意義，如何激活MAPK信號(hào)通路和調(diào)節(jié)下游神經(jīng)營(yíng)養(yǎng)因子表達(dá)的機(jī)制仍不清楚。

3小結(jié)

利魯唑?qū)劝彼嵬挥|傳遞的抑制效應(yīng)在其神經(jīng)保護(hù)作用機(jī)制中具有重要意義，作用位點(diǎn)涵蓋了突觸前、突觸間隙及突觸后。利魯唑?qū)劝彼嵬挥|傳遞的抑制能直接降低神經(jīng)元超興奮，而利魯唑抑制持續(xù)性鈉電流、增強(qiáng)鈣依賴性鉀電流、增加突觸后GABA受體的反應(yīng)性的能力同樣對(duì)降低神經(jīng)元超興奮具有協(xié)同作用，從而保護(hù)神經(jīng)元免受興奮毒性損傷。此外，利魯唑?qū)ι窠?jīng)營(yíng)養(yǎng)因子基因及蛋白表達(dá)水平的調(diào)節(jié)作用將促進(jìn)神經(jīng)元的發(fā)育、分化、生長(zhǎng)和存活。這些研究對(duì)了解利魯唑的神經(jīng)保護(hù)作用提供了重要線索，而對(duì)利魯唑已知及潛在作用機(jī)制更深入的探索將為該藥在臨床上的應(yīng)用提供更多幫助。

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Riluzole′s Neuroprotective Effect and the Mechanisms

HANGuo-ying,LIChun-yan,SHIHai-bo,YINShan-kai.

(DepartmentofOtorhinolaryngology,ShanghaiSixthPeople′sHospital,Shanghai200233,China)

Abstract:Riluzole(2-p-aminophenyl-6-substituent-benzothiazole) is a benzothiazole compound,which has definite neuroprotective effect.The main mechanisms underlying this effect are likely to be multifaceted,involving suppressing glutamate neurotransmission and neuronal hyperexcitation,promoting the expressing of nerve growth factors via the function of a variety of receptors and related ion channel,protecting neurons from toxicological damage. Here is to make a review of neuroprotective effect and mechanisms of riluzole to provide a basis for further study.

Key words:Riluzole; Neuroprotection; Gluamate

收稿日期：2014-05-04修回日期：2014-08-29編輯：伊姍

基金項(xiàng)目：國(guó)家自然科學(xué)基金(81100718)

doi：10.3969/j.issn.1006-2084.2015.08.004

中圖分類號(hào)：R971

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)08-1353-04