综述 Review

与癫痫有关的细胞信号通路的研究现状

Published at: 2014年第34卷第1期

臧玉静 1 , 赵春玲 1
1 泸州医学院生理教研室,四川 泸州 646000
通讯作者 春玲 赵 Email: zhchlzth@21cn.com
DOI: 10.3978/j.issn.2095-6959.10.3978/j.issn.2095-6959.2014.01.017
基金:

摘要

细胞信号通路调控着生物的生长、发育并参与疾病的发生。研究表明,与癫痫有关的信号通路主要有磷脂酰肌醇3-激酶/丝苏氨酸蛋白激酶、哺乳动物雷帕霉素靶蛋白、Wnt等,它们通过调控蛋白质的合成代谢、细胞的增殖和凋亡影响癫痫的病理变化。本文就与癫痫的细胞信号通路的研究进展作一综述。


Research progress in signaling pathways related to epilepsy

Abstract

Signaling pathways are involved in biological growth and development, and are closely related to the occurrence of diseases. Recent studies have shown that there are several signaling pathways are associated with epilepsy, such as phosphoinositide3-kinase/ serine-threonine kinase (PI3K/Akt), the mammalian target of rapamycin (mTOR) and Wnt. These signaling pathways are involved in the pathologic changes of epilepsy through regulation of protein synthesis, cell proliferation and apoptosis. This article summarizes the progresses regarding epilepsy and the associated signaling pathways.

癫痫是以神经元兴奋和抑制失衡引起的过度兴奋导致神经元群同步异常放电为特征的神经系统疾病,发病率为0.3%~0.5%,患病率5‰~10‰[1]。目前全世界约有5千万人患有癫痫[2],有30%~40%的患者使用药物治疗后病情依然不能得到控制[3]。癫痫的发病机制十分复杂,至今未完全阐明,这也是临床治愈率有限的原因。目前认为癫痫的发病机制与离子通道、神经递质、免疫、神经胶质细胞的改变有关[4-7]。细胞信号通路通过介导相关基因的表达调控细胞的存活、增殖、凋亡参与疾病的发生。近些年的研究提示多种信号通路可能与癫痫有关,如磷酸酰肌醇3-激酶(phosphoinositide-3-kinase,PI3K)、哺乳动物雷帕霉素靶蛋白(the mammalian target of rapamycin,mTOR)、Wnt、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、核转录因子(nuclear factor,NF) -κB等。因此笔者就与癫痫有关的信号通路作一综述。

1  PI3K/Akt信号通路

PI3K属于脂类激酶。Akt即蛋白激酶B(PKB),是病毒原癌基因v-Akt的同源物,也是 PI3K的下游作用靶物。

1.1  PI3K/Akt信号通路作用机制

PI3K/Akt信号通路的活化路径概括如下:胞外因子如生长因子可与相应的酪氨酸受体结合,引导PI3K转移至附近的浆膜,活化的PI3K可产生第二信使磷脂酰肌醇二磷酸[phosphtidyli-nositol(4, 5)-bisphosphate,PIP2]进而产生 肌醇三磷酸(phosphatidylinositol-3, 4, 5-trisphosphate,PIP3),PIP3分别与Akt和磷脂酰肌醇依赖激酶 (phosphoinositide-dependent kinase 1,PDK1)的PH结构域结合,将二者从细胞质转移至细胞膜,PDK1磷酸化Akt蛋白的Thr308位点,PDK2磷酸化其Ser473位点,活化的Akt通过磷酸化作用激活或抑制下游靶蛋白Bad,caspase-9,NF-κB,GSK-3β,Mdm2,Forkhead,mTOR,Par-4,P21,P53等实现生物学效应。

1.2  PI3K/Akt信号通路与癫痫

在戊四氮(pentylenetetrazol,PTZ)致痫的模型中存在海马神经元的氧化损伤[8]和Akt蛋白活化[9],匹鲁卡品致大鼠癫痫的潜伏期Akt蛋白磷酸化增强[10]。二氮嗪通过降低羟自由基(malondialdehyde,MDA)的活性并提高超氧化物歧化酶(superoxide dismutases,SOD)的水平减少PTZ致痫大鼠的氧化损伤,重组人红细胞生成素通过提高Akt蛋白的活性减少海马神经元的坏死和癫痫放电的发生,达到抗凋亡和保护神经元的效果。PI3K/Akt通路抑制剂(LY294002或渥曼青霉素)能阻断该通路并减弱MDA和SOD的变化水平或减轻抗凋亡和保护神经元的作用,说明二氮嗪的抗氧化损伤作用和重组人红细胞生成素的保护神经元作用都是通过PI3K/Akt途径实现的[8-9]。褪黑激素通过持续活化Akt蛋白增加其磷酸化位点,促进胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)的表达,减少海人酸(kainic acid)诱导的神经元死亡[11]。研究[12]表明活化的PI3K/Akt通路可以减少细胞钙离子内流,细胞内钙离子稳态失衡也是影响癫痫病理变化的因素之一。在海马神经元细胞培养和海人酸诱导大鼠癫痫发作的实验中发现红细胞生成素可激活海马神经元的PI3K/Akt通路,通过减少海马神经元钙离子内流减弱海马神经元兴奋性,降低海马神经元的损伤程度。使用LY294002可阻断红细胞生成素对钙离子流速的抑制效应[12]。有学者[13]认为红细胞生成素保护神经元的机制可能是通过PI3K/Akt信号通路调控caspase-9和X-连锁凋亡抑制蛋白介导线粒体凋亡实现的。

2  mTOR信号通路

mTOR是一种丝/苏氨酸蛋白激酶,属于磷酯酰肌醇激酶相关激酶PI3K家族成员。

2.1  mTOR信号通路作用机制

mTOR主要参与的信号通路有:1)PI3K/Akt/mTOR信号通路,该通路与细胞生长增殖有关。Akt,Rheb(Ras homolog enriched in brain)和TSC1/ TSC2(the tuberous sclerosis compel 1/2)是mTOR的上游调节因子。活化的Akt将PRAS40磷酸化,解除其对mTORC1的抑制作用,激活mTORC1。活化的mTOR通过磷酸化其下游效应分子真核细胞翻译起始因子4E结合蛋白1(the Eif4E-binding protein 1,4E-BP1)和核糖体蛋白S6激酶(ribosomal protein S6 kinases,S6Ks),促进延长因子-1(elongation fator-1,EF-1)、poly(A)结合蛋白等蛋白质翻译及表达,参与调控细胞生长和增殖。另外Akt还间接影响mTOR: Akt抑制TSC的表达,TSC进一步负调控小G蛋白Rheb,Rheb有正性调节mTORC1的作用。2)LKB1/AMPK/TSC/mTORC1通路主要调节细胞的能量代谢。在缺氧、营养匮乏、能量低下时,AMPK直接磷酸化TSC2,促进TSC1/TSC2复合物的形成,抑制Rheb的活性进而抑制mTORC1的活性,减少细胞内蛋白质合成和细胞分裂增殖。mTOR的负性调节因子TSC1/TSC2具有编码蛋白调节细胞的功能,通过mTOR信号级联反应,调节细胞生长和增殖。

2.2  mTOR信号通路与癫痫

PTZ和海人酸致痫的动物模型通过上调PI3K/Akt的活性激活mTOR信号通路[14-15]。敲除TSC1基因或者TSC1基因突变引起mTORC1活化,最终导致神经元的兴奋与抑制失衡,引发癫痫[16-17]。敲除抑癌基因PTEN(phosphatase and tensin homolog deleted onchromosome ten)能过度激活mTOR信号通路导致神经元过度兴奋和苔状纤维发芽,并引发癫痫[18]。张笋[19]在慢性癫痫发作的动物模型中发现大鼠海马和前额叶皮层组织内mTORmRNA,4EBP1mRNA表达明显降低。因此,mTOR信号通路与癫痫的发生机制尚不明确。但多项实验[13,16,20]表明,抑制mTOR信号通路可以阻止可能与致痫有关的异常改变。癫痫发作后使用雷帕霉素治疗可逆转谷氨酸神经递质的增加、癫痫易感性、自闭症之类的行为,也可抑制苔状纤维发芽,但不能减少颗粒细胞的异常增殖和神经元丢失。在结节硬化症的动物模型中,雷帕霉素能减少mTORC1 活化水平[17],有效抑制癫痫发作,并延长癫痫发作动物的存活时间[21]。低氧诱导慢性癫痫发作后使用雷帕霉素可减少其发作频率和发作时间[22]。有实验[16]表明姜黄素和白藜芦醇也可抑制mTOR信号通路,姜黄素可延缓外伤性癫痫的发作时间。生酮饮食治疗也可抑制海人酸致痫引起的海马神经元mTOR信号通路活化,减轻癫痫发作,但具体机制还存在争议[23]。长期使用雷帕霉素治疗结节性硬化症有减轻癫痫发作的效果,一旦停药则能引起mTOR信号通路的过度激活,再次引起癫痫发作[16]。雷帕霉素的治疗作用具有双面效果,其作用机制还需进一步探索。

3  Wnt信号通路

Wnt信号通路具有进化保守性,广泛存在于各种物种。人类的wnt基因位于12q13,编码分泌型蛋白。人和鼠的基因组中已经发现有19种wnt基因,分别命名为wnt-1,wnt-2,wnt-3a等。

3.1  Wnt信号通路作用机制

Wnt信号通路激活包括以下3个路径:经典通路(Wnt/β-catenin通路);Wnt/Ca2+通路;Wnt/PCP通路即平面细胞极化通路(planar cell polarity),又称为JNK通路。其中,经典的Wnt/β-catenin通路尤其受到学者们的关注。该通路未被激活时由APC蛋白、轴蛋白(Axin)、糖原合成激酶-3β(glycogen synthase,Gsk-3β)组成的复合物磷酸化β-catenin的特定位点,之后β-catenin经泛素化降解,在胞质中维持较低浓度。Wnt3a等激活物与细胞表面的卷曲蛋白受体及低密度脂蛋白受体关联蛋白(low density lipoprotein-related protein 5/6,LRP5/6)结合,抑制细胞内Gsk-3β活性,阻止其下游的β-catenin降解,使之在胞质内聚集并进入核内,与T细胞因子/淋巴样增强因子结合(T-cell factor/ lymphoid enhancing factor,TCF/LEF)而诱导靶基因细胞周期蛋白的转录,引起细胞循环周期失控,导致细胞过度增殖。

3.2  Wnt信号通路与癫痫

研究[24-25]发现,匹鲁卡品诱导的癫痫动物模型海马CA3区锥体细胞层β-catenin表达增强,电惊厥癫痫大鼠海马区Wnt2和β-catenin的表达明显增加。探讨癫痫发作机制的动物实验研究[26-28]表明,无论是急性癫痫还是慢性癫痫,其发作都有新海马神经元的发生。人类癫痫发作是否促进海马神经发生依旧存在争议[29],但现有的证据证实人类海马组织中存在Wnt3a和Wnt7a。Avila等[30]在细胞培养海马神经元的实验中发现Wnt3a参与中枢神经元递质的传递。Wnt3a和Wnt7a与人类颞叶癫痫海马神经发生的关系还不明确,需要深入研究。

此外,有研究[31]发现Wnt信号通路抑制物DKK-1在健康人脑组织中表达较少,而在颞叶癫痫脑组织中过表达。Busceti等[31]发现颞叶癫痫患者的海马中DKK-1的表达比正常对照组和部分性癫痫发作患者更强,证实了DKK-1与神经元死亡有十分密切的联系,具有促进神经元损伤的作用。

4  MAPK通路

4.1  MAPK作用机制

MAPK属于丝氨酸/苏氨酸激酶,其联级反应包括4种下游途径:细胞外信号调节激酶(extracelluar signal-regulated kinse,ERK)、c-Jun氨基酸末端激酶(c-Jun N-terminal kinase,JNK)、P38和ERK5/BMK1(big MAP kinase)。MAPK信号通路的激活途径:细胞有丝分裂原磷酸化MAPK激酶的激酶(mitogen-activated protein kinase kinase kinase,MAKKK),活化的MAKKK磷酸化MAPK激酶(mitogen-activated protein kinase kinase,MAKK),进而激活MAPK,使其进入细胞核磷酸化转录因子TCF,活化转录因子2(activating transcription factor 2,ATF-2),c-Myc以及c-Jun,调节细胞的生长和分化。其中P38与癫痫的发作有密切联系。P38 MAPK主要是由炎症因子和环境压力激活。P38 MAPK联级反应:PAK→MLK→MKK/3/6/4→p38MAPK。活化的P38 MAPK通过上调转录因子ATF2,MEF2C(肌细胞增强因子2C),CHOP10(C/EBP同源蛋白)等基因的表达,控制细胞的增殖、分化及凋亡。

4.2  MAPK与癫痫

PTZ或匹鲁卡品诱导急性大鼠癫痫发作的模型中P38 MAPK磷酸化水平高于正常对照组,说明P38 MAPK在癫痫模型中被激活[10,32]。进一步研究[10]发现p38 MAPK磷酸化水平在癫痫发作后1~2 h内明显升高。抑制p38 MAPK可以减少癫痫诱导的锥体细胞缺失、细胞变性、神经元损伤[33]和海马神经元退化[34],显然MAPK的活化与海马神经元损伤有关。

5  NF-κB通路

NF-κB广泛存在于神经细胞中,特别是大鼠皮质和海马区,参与免疫应激反应、炎症反应及细胞的增殖与凋亡。

5.1  NF-κB作用机制

NF-κB正常情况下位于胞质中,由3个亚族组成:p50,p60和IκB。NF-κB被基本认同的激活途径是:非活化状态下胞质中的NF-κB与IκB相结合,外界刺激可激活 IκB激酶进而磷酸化IκB,解除其对NF-κB的抑制作用,直接激活NF-κB,活化的NF-κB暴露出核定位序列迅速进入细胞核,启动白介素1(interleukin 1,IL-1)、白介素6(interleukin 1,IL-6)、白介素8(interleukin 8,IL-8)、白介素12(interleukin 12,IL-12)等细胞因子。活化的NF-κB也可开启胶质细胞原纤维酸性蛋白和神经元型一氧化氮合酶基因转录。

5.2  NF-κB与癫痫

已有研究[35-43]显示NF-κB在癫痫、帕金森症等神经退行性疾病中有神经保护作用。黄亚玲等[35]的研究证明NF-κB在育鼠癫痫模型中有促进海马神经元发生的作用;细胞培养实验表明激活NF-κB可以减少神经元细胞凋亡。但在海人酸诱导致痫的动物模型中,海马神经元退化的CA1区存在NF-κB被激活的现象[36],NF-κB也存在于癫痫发作后的星型胶质细胞和神经元细胞中[37]。在CA3区活化的NF-κB可上调一氧化氮合酶基因的表达引起海马神经元的死亡[38]。在癫痫患儿的外周血单个红细胞中NF-κB活化与癫痫发作的严重程度成正相关[39]。故NF-κB在癫痫疾病发展过程中是促进存活还是促进损伤仍需要继续探究。Li等[40]在颞叶癫痫患者的神经胶质细胞中发现NF-κB表达上调;Lubin等[41]在海人酸致痫的大鼠中发现NF-κB的表达增高,使用NF-κB信号通路抑制剂后,癫痫的潜伏期缩短,易感性增强,病情加重;不过也有人[42]证实NF-κB抑制剂吡咯烷二硫代氨基甲酸盐(pyrrolidine dithiocarbamate salt,PDTC)可减少癫痫敏感性,但对大脑损伤和动物死亡率并没有影响;PDTC还可通过降低糖蛋白的表达下调海马CA3区NF-κB的活性[43],证实了NF-κB的活化与癫痫易感性有关。地卓西平可选择性阻断海人酸诱导的海马CA1区NF-κB活化和神经元死亡,对CA3区和海马门区神经毒性却没有保护作用[36]。使用不同的NF-κB抑制剂对癫痫的影响截然不同,这与NF-κB在神经保护方面机制有关,需要人们更进一步地探索。

6  Notch通路

Notch信号通路在中枢神经系统的发育中有重要的调控作用,参与神经干细胞的形成、细胞命运和神经元细胞有丝分裂后期神经突起的生长[44-45]

6.1  Notch通路作用机制

哺乳动物体内有4种Notch受体(Notch1,Notch2,Notch3,Notch4),5种Notch配体(Delta,Dll1,Dll3,Dll4,Serrate)。Notch通路的激活是由两相邻细胞的Notch受体和配体结合引起。活化后受体胞外域的金属蛋白酶TACE切割位点暴露,在γ-分泌酶的作用下水解释放出NICD (Notch intracellulardomain 1)片段,NICD进入细胞核与CSL(CBF-1,suppressor of hairless,Lag的合称)转录因子作用进而激活下游基因转录,影响细胞分化、增殖和凋亡。

6.2  Notch通路与癫痫

Notch表达减少引起神经干细胞增殖[46],Notch过表达则造成生长停滞[47]。Notch对神经干细胞的调控具有双向作用。缺氧诱导出生后大鼠脑损伤可引起Notch通路活化[48];尸检发现人类癫痫伴海马硬化患者中存在Notch1;胚胎发育过程中Notch基因缺失导致小鼠死亡[49]。Hortopan等[50]证实Notch信号通路失调可引起斑马鱼癫痫发作;

他们认为这与Notch通路的异常表达和神经系统发育障碍有关[51]。海人酸致痫的动物模型和人类癫痫病变组织中都存在Notch的活化,而且Notch的活化进一步促进CA1区锥体神经元的兴奋。使用Notch通路抑制剂DAPT(分泌酶抑制剂)可抑制急性癫痫发作,并抑制细胞培养海马神经元突触囊泡的增殖[52],也可减少缺氧诱导的炎症介质表达上调[48]。Notch通路与癫痫机制的关系还需进一步证实。

7  结   语

尽管医务工作者已为癫痫的防治做了大量的研究工作,但现有的科学研究和医疗技术还不能有效地阻止癫痫的发生和发展。因此,探索癫痫的致病机制及寻找新的治疗方法和靶向药物,仍然是未来重要的研究课题。目前已经发现多种信号通路与癫痫相关,这些信号通路的激活或下调引起下游靶基因的改变,部分靶基因又可反馈调节上游通路,且多种信号通路间相互关联,共同调节细胞的功能和凋亡等,最终影响癫痫的发生、发展、疗效和转归等。显然,目前的研究尚不能完全揭示这些信号通路参与癫痫的具体机制。因此,深入、透彻地了解各种信号通路与癫痫的关系,将为临床治疗方面提供更多更有效的治疗策略,并推动疾病分子水平的研究进程。


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引用本文: 玉静 臧, 春玲 赵. 与癫痫有关的细胞信号通路的研究现状[J]. 临床与病理杂志, 2014, 34(1): 99-105.
Cite this article as: ZANG Yujing, ZHAO Chunling . Research progress in signaling pathways related to epilepsy [J]. Journal of Clinical and Pathological Research, 2014, 34(1): 99-105.