修回日期: 2014-10-08
接受日期: 2014-10-15
在线出版日期: 2014-11-28
肝性脑病(hepatic encephalopathy, HE)是由慢性或急性肝脏疾病引起的神经精神症候群的一种医学现象. 神经甾体是以胆固醇及其前体为原料, 由中枢神经系统多种细胞(神经元、少突胶质细胞、星形胶质细胞)合成. 神经甾体通过基因和非基因效应参与HE的病理生理. 一方面, 神经甾体结合并调节不同的神经元膜受体, 包括γ-氨基丁酸A受体(gamma amino butyric acid-A receptor, GABA-A)、N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor, NMDA)、5-羟色胺3(5-hydroxytryptamine 3, 5-HT3)受体及阿片受体等; 另一方面, 神经甾体结合于细胞内受体来调节基因表达. 值得一提的是, 神经甾体通过抑制海马突触活性的长时程增强效应(long-term potentiation, LTP)参与HE的病理生理. 神经甾体有望为肝性脑病治疗提供新的途径.
核心提示: 神经甾体的基因、非基因效应及抑制海马突触活性的长时程增强效应(long-term potentiation)等在肝性脑病(hepatic encephalo-pathy, HE)发生发展中的作用提示可以研究开发以神经甾体合成酶或基因型和非基因型神经甾体受体调节剂为靶点的药物为HE的治疗提供新的途径.
引文著录: 王小英, 谢瑞霞, 张建刚, 张德奎. 神经甾体在肝性脑病中的研究进展. 世界华人消化杂志 2014; 22(33): 5086-5091
Revised: October 8, 2014
Accepted: October 15, 2014
Published online: November 28, 2014
Hepatic encephalopathy (HE) is a neuropsychiatric manifestation of chronic or acute liver disease. Neurosteroids are synthesized from cholesterol and its precursors by glial cells, oligodendrocytes and neurons in the brain. The mechanisms by which neurosteroids affect brain function may involve both genetic and non-genetic effects. On one hand, neurosteroids bind and modulate different types of neuronal membrane receptors, including gamma-amino butyric acid-A receptor (GABA-A), N-methyl-D-aspartic acid receptor (NMDA), 5-hydroxytryptamine 3 (5-HT3) and opioid receptors which have been showed to be involved in HE. On the other hand, some neurosteroids bind to intracellular receptors through which they also regulate gene expression. Of note, neurosteroids play a role in the pathogenesis of HE through inhibiting long-term potentiation. Neurosteroids might provide a new avenue for HE treatment.
- Citation: Wang XY, Xie RX, Zhang JG, Zhang DK. Role of neurosteroids in hepatic encephalopathy. Shijie Huaren Xiaohua Zazhi 2014; 22(33): 5086-5091
- URL: https://www.wjgnet.com/1009-3079/full/v22/i33/5086.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v22.i33.5086
肝性脑病(hepatic encephalopathy, HE)是由慢性或急性肝脏疾病引起的神经精神症候群的一种医学现象, 其特点是精神、智力和认知异常, 情绪、情感和行为障碍, 严重时可因脑水肿及颅内压增高导致昏迷或死亡[1-3]. 临床上一旦发生HE, 病死率在50%-90%[4]. HE的发病机制尚不完全清楚, 简要地说, 在HE的发病机制中第一种假说集中于某些物质在血液中异常蓄积, 如氨或锰, 氨中毒学说已被广泛接受[5,6]. 然而, 有证据[7]表明其他因素也参与HE病理生理, 如神经递质传递异常、星形胶质细胞损伤(可能与细胞水肿有关)及小胶质细胞活化(神经炎症). 近期, 越来越多的研究[8-10]证明中枢神经系统神经甾体的产生在HE病理生理发展中扮演重要角色. 现将神经甾体在HE的研究进展作一综述.
以往很长时间都认为肾上腺皮质、性腺和胎盘是甾体激素产生的唯一来源, 但相关研究[11-14]表明在摘除性腺和肾上腺大鼠的大脑中仍然测得高浓度的甾体激素, 证实甾体激素也可在大脑中合成, 这种中枢神经系统合成的甾体激素称之为神经甾体. 通过免疫组织化学、免疫印迹法和原位杂交技术已经证实大脑中存在神经甾体合成的关键酶, 包括细胞色素P450侧链裂解酶(cytochrome P450 side-chain cleavage enzyme, P450scc)、3α-羟甾醇脱氢酶、3β-羟甾醇脱氢酶、细胞色素17α-羟化酶(cytochrome P450 17α-hydroxylase, P450c17)、5α-还原酶及羟磺基转移酶等. 神经甾体合成酶在大脑中表达, 进一步佐证了中枢神经系统产生神经甾体[15,16]. 根据结构特点, 神经甾体分为孕烷神经甾体[如别孕烯醇酮、四氢脱氧皮质酮(allotetrahydrodeoxycorticosterone, THDOC)]、雄烷神经甾体(如雄甾烷二醇)、硫酸盐神经甾体[如孕烯醇酮硫酸盐(pregnenolone sulfate, PS)以及脱氢表雄酮硫酸盐(dehydroepiandrosterone sulfate, DHEAS)][17].
早期研究[18,19]认为神经甾体是以胆固醇及其前体为原料, 主要合成场所是神经胶质细胞, 如少突胶质细胞、星形胶质细胞. 然而, 最新的研究[20-22]表明兴奋性神经元在神经甾体合成中起重要作用, 发现包括海马椎体神经元和新皮层椎体神经元高表达甾体合成急性调节蛋白(steroidogenic acute regulatory protein, StAR)、5α-还原酶及编码P450scc的CYP11A1基因; 除此之外, 实验也证明神经甾体5α-还原性免疫反应发生在兴奋性神经元, 而不是在中间神经元和神经胶质细胞.
神经甾体以胆固醇及其前体为原料通过一系列步骤生成, 包括胆固醇在StAR作用下转运至线粒体外膜, 胆固醇通过转运蛋白(translocator protein, TSPO)穿梭入线粒体内膜, 并在P450scc的作用下转化为孕烯醇酮, 孕烯醇酮出线粒体进入内质网再进一步转化为别孕烯醇酮、THDOC等神经甾体, 进而成为γ-氨基丁酸A受体(gamma amino butyric acid-A receptor, GABA-A)等的增效或抑制剂[8,23-25]. 孕烯醇酮是内源性神经甾体别孕烯醇酮和THDOC等的前体[17]. 胆固醇通过TSPO进入线粒体内膜是一个限速步骤, 且TSPO在神经甾体合成中举足轻重. TSPO是一个多蛋白复合体, 包括电压依赖性阴离子通道(voltage-dependent anion channel, VDAC)和腺嘌呤核苷酸转运体(adenine nucleotide carrier, ANT). TSPO以往称之为边缘性苯二氮卓类受体(peripheral-type benzodiazepine receptor, PTBR), 临床上通过激活TSPO促进神经甾体合成[8,26-28].
肝衰竭导致血氨和锰等神经毒性物质在大脑中蓄积, 研究证明血氨和锰可激活TSPO, 继而使中枢神经系统神经甾体合成. HE患者或实验性HE动物模型在高血氨情况下, TSPO基因表达增加[29]; 此外, 高浓度氨培养的星形胶质细胞, TSPO配体[3H]PK11195结合位点密度增加[30]. 因为甾体激素能自由通过血脑屏障, 所以存在于外周的神经甾体前体可能也影响大脑神经甾体合成[23]; 最后, 近期有证据[8]显示HE神经炎性也涉及神经甾体合成.
第一个提出神经甾体与HE发病机制有关的是Zaman[31]. 之后越来越多的证据表明人类HE和实验性动物HE模型大脑神经甾体存在变化. 硫代乙酰胺(thioacetamide, TAA)诱导的小鼠急性肝衰竭(acute liver failure, ALF)模型, 发现大脑皮层神经甾体前体孕酮(progesterone, Prog)增加[32]. 此外在肝昏迷死亡的患者额叶皮层也发现Prog增加[33], 中枢神经系统Prog的增加也伴随别孕烯醇酮和THDOC的增加. HE患者大脑神经甾体积聚, 通过不同机制影响中枢神经系统. 某些神经甾体增强或减弱GABA-A的效应, 另一些神经甾体可能调节σ受体或N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor, NMDA)等, 称之为非基因组效应; 而某些神经甾体结合于细胞内受体, 作为转录因子调节基因表达影响神经元功能, 称之为基因组效应[8,16,34]. 神经甾体通过不同神经递质受体内源性调节神经元兴奋性, 为开发HE治疗方法提供可能.
GABA是中枢神经系统主要的抑制性神经递质, 近三十年, GABA能增强效应的提出, 用来解释HE的病理生理[35-37]. 但HE时中枢神经系统神经元群体和他们的GABA能传入受到的影响仍然不完全清楚, 原因可能是由于多种类型GABA能中间神经元的存在或种类繁多的GABA-A受体对大脑电路控制的复杂性, 也可能是由于病理条件的不同的影响, 但至今尚未完全确定[38]. GABA-A受体是由五个亚基组成的配体门控Cl-通道. GABA-A受体被激活, 可选择性的让Cl-通过, 引起神经元超级化或去极化, 正性或负性调节GABA-A受体, 从而抑制或兴奋神经元[39,40]. 研究证实GABA-A受体正性变构调节剂(抑制性神经甾体、麻醉药、苯二氮卓类和组胺等)和GABA-A受体负性变构调节剂(兴奋性神经甾体、RO15-4513等)都影响HE的病理生理. 突触后GABA-A受体是神经甾体结合并正性或负性调节的最主要位点. 既往研究[38]认为别孕烯醇酮等GABA-A受体正性变构调节剂作用于GABA-A受体的GABA结合位点, 增加GABA对GABA-A受体的敏感性, 从而提高GABA能抑制效应; 随后, 研究认为氟马西尼(苯二氮卓类受体拮抗剂)减轻HE症状可能与别孕烯醇酮正性调节GABA-A受体苯二氮卓类结合位点使结合位点作用显著增强有关, 说明神经甾体也积极正性调节GABA-A受体苯二氮卓类结合位点. 产生于中枢神经系统的神经甾体, 如别孕烯醇酮、脱氧皮质酮(deoxycorticosterone, DOC)、脱氢表雄酮(dehydroepiandrosterone, DHEA)及睾酮, 通过与一个或多个GABA-A受体的结合位点相互作用致使Cl-通道开放频率增加, 从而增强GABA能神经传递, 积极的正性调节GABA-A受体, 产生抑制神经元兴奋性的作用, 产生抗焦虑、抗惊厥、认知功能损伤及镇静等行为. 另一些神经甾体则表现出弱的GABA-A受体拮抗作用, 包括PS、DHEAS等硫酸盐神经甾体结合于GABA-A受体, 使Cl-顺浓度差流向细胞外, 引起去极化, 兴奋神经元[16,25,41,42]. 这表明兴奋性神经甾体可反转抑制性神经甾体正性调节而造成的损伤认知能力, 进而达到治疗作用.
神经甾体影响中枢神经系统的一些神经元膜受体, 这些受体除了GABA-A受体还包括NMDA受体、甘氨酸受体、5-羟色胺3(5-hydroxytryptamine 3, 5-HT3)受体、阿片受体等. 神经甾体可能通过调节涉及HE突触后5-HT3、NMDA、甘氨酸、阿片受体来直接影响神经传递系统. GABA-A受体激活并调节NMDA受体, 随之又激活谷氨酸-一氧化氮-环磷酸鸟苷通路[glutamate-nitric oxide (NO)-cGMP pathway], 说明GABA-A受体与其他受体相互作用[43]. 近期的研究显示大鼠脑部抑制性神经甾体积聚使GABA能增强, 其与GABA-A受体与NMDA-谷氨酸-NO-cGMP通路协同作用有关[8,43]. 西班牙科学家用含铵的食物喂养Wistar大鼠诱导高血氨模型, 通过微透析探头测定活体大鼠小脑神经甾体以及细胞外cGMP和瓜氨酸浓度, 然后评估NMDA对谷氨酸-NO-cGMP通路活化的影响, 发现高血氨通过上调TSPO改变一些神经甾体的浓度, 神经甾体调节NMDA-GABA-A受体或σ受体, 进而破坏谷氨酸-NO-cGMP通路, 导致学习能力下降[44].
在HE动物模型中, DHEAS(可降低GABA能)浓度下降有助于啮齿动物中缝背核5-HT神经元5-HT3发射率抑制, 反之大鼠脑部DHEAS浓度升高致使5-HT神经元发射率提高, 从而显著减轻胆汁淤积性肝硬化大鼠运动活动异常[45]. 表明DHEAS降低GABA诱导的5-HT神经元发射率抑制.
血氨诱导神经甾体合成从而损伤海马突触活性的长时程增强(long term potentiation, LTP), LTP是与学习记忆密切相关的神经突触可塑性的生物学基础. 尽管神经甾体损伤LTP的机制尚不清楚, 但先前的研究[46,47]发现激活NMDA受体非常重要. Izumi等[48]通过高血氨诱导HE大鼠模型, 发现100 µmol/L浓度氨损伤LTP, 而使用针对5α-还原性神经甾体的抗体, 发现100 µmol/L浓度的氨同时敏锐地增强神经甾体在大鼠的海马CA1区切片锥体神经元的免疫染色. 而这一增强的免疫染色可以被5α-还原酶(别孕烯醇酮合成的关键酶)的选择性抑制剂非那雄胺所阻断, 非那雄胺也同时阻断100 µmol/L浓度氨导致的LTP损伤. 这些结果显示增强GABA作用的神经甾体(在锥体神经元局部合成)对血氨介导的突触功能紊乱有显著作用.
神经甾体除了通过膜受体快速非基因的调节, 一些神经甾体可通过核受体调节大脑基因表达来触发基因效应[49]. 众多证据显示星形胶质细胞和神经元蛋白基因编码的关键表达在HE大脑改变. 如星形胶质细胞内胶质纤维酸性蛋白(glial fibrillary acidic protein, GFAP), 星形胶质细胞胞内葡萄糖转运体(astrocytic transporter for glucose, GLUT-1)、甘氨酸的载体(glycine, GLYT-1)及水通道蛋白Ⅳ等基因表达发生改变[33]. 但迄今为止其具体分子机制和信号途径尚不清楚, 神经甾体在脑内积聚, 可能导致HE患者上述物质基因表达的改变. 如别孕烯醇酮和其他神经甾体作为孕烷核X受体的配体影响基因表达, 就此我们认为神经甾体调节中枢神经系统的基因表达[50]. 不像毫微摩尔浓度级神经甾体激活膜受体, 核受体的激活需要微摩尔浓度级的配体激活基因表达[8].
近年来, 越来越多的证据显示人类HE和实验性HE动物模型脑内神经甾体积聚. 这些神经甾体可能涉及调节神经传递和基因表达. 神经甾体的变化可能为HE一些未明确的现象提供更好的解释, 如GABA能增加的概念. 尽管一些神经甾体对血氨、锰积聚及促炎因子引起的细胞毒性效应有保护作用, 但一部分神经甾体也有不利作用, 如神经传递, 可导致精神、行为、运动等的损伤. 对HE而言, 神经甾体是否对脑水肿有利或不利仍需进一步研究其病理生理机制. 研究开发以神经甾体合成酶或基因型和非基因型神经甾体受体调节剂为靶点的药物为HE的治疗提供新的途径.
肝性脑病(hepatic encephalopathy, HE)是由慢性或急性肝脏疾病引起的神经精神症候群的一种医学现象. HE的发病机制尚不完全清楚, 简要地说, 在HE的发病机制中第一种假说集中于某些物质在血液中异常蓄积, 如氨或锰, 氨中毒学说已被广泛接受. 尽管氨中毒学说在HE发生发展中起核心作用, 然而近期, 越来越多的学者认为中枢神经系统神经甾体通过基因与非基因效应参与HE病理生理.
李胜, 研究员, 山东省肿瘤防治研究院肝胆外科
越来越多研究表明HE时神经甾体一方面结合并调节不同的神经元膜受体, 如γ-氨基丁酸A受体(gamma amino butyric acid-A receptor, GABA-A)、N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor, NMDA)等; 另一方面神经甾体结合于细胞内受体来调节基因表达; 神经甾体还可通过抑制海马突触活性的长时程增强效应(long term potentiation, LTP)参与HE的病理生理. 但具体作用机制尚不清楚, 亟待进一步研究.
HE发病机制深入的研究为临床治疗HE提供重要依据, 近年来学者倾向于从分子水平、信号通路等方面研究HE的病理生理.
本文从神经甾体的基因、非基因效应及抑制海马突触活性的LTP等方面回顾了近年来关于神经甾体在HE发生发展中的作用.
研究开发以神经甾体合成酶或基因型和非基因型神经甾体受体调节剂为靶点的药物为HE的治疗提供新的途径.
LTP: 作为突触可塑性研究模型, 认为是与学习记忆密切相关的神经突触可塑性的生物学基础.
文章思路清晰, 对神经甾体在HE中的研究做了一个综述, 对HE时神经甾体的变化及神经甾体对中枢神经系统影响的深入研究, 有助于促进HE病因学研究和开辟HE诊治的新视角.
编辑:郭鹏 电编:都珍珍
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