Altered glial-neuronal crosstalk: Cornerstone in the pathogenesis of hepatic encephalopathy
Altered glial-neuronal crosstalk: Cornerstone in the pathogenesis of hepatic encephalopathy
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DOI：
10.1016/j.neuint.2010.03.012
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发表时间：
2010-11-01
影响因子：
4.2
通讯作者：
Butterworth, Roger F.
中科院分区：
文献类型：
--
作者：
Butterworth, Roger F.
肝性脑病（HE）是肝功能衰竭的一种严重的神经精神并发症，其神经病理学特征是星形胶质细胞肿胀、小胶质细胞活化和阿尔茨海默氏II型星形胶质细胞增多。HE脑中的分子研究揭示了编码关键星形胶质细胞蛋白的基因表达的改变，包括GFAP和谷氨酸转运蛋白EEAT-2表达的早期损失，伴随着星形胶质细胞/小胶质细胞线粒体苯二氮卓受体（MBR）的增加。EAAT-2表达减少导致谷氨酸转运减少和星形胶质细胞和神经元之间谷氨酸-谷氨酰胺循环受损，以及细胞外谷氨酸增加，NMDA受体介导的cGMP-NO信号转导途径活化，以及关键星形胶质细胞蛋白如谷氨酰胺合成酶（GS）和MBR上酪氨酸残基的硝化。GS是唯一负责清除大脑中多余的氨。氨诱导的星形胶质细胞和/或小胶质细胞中MBR的活化导致刺激神经类固醇如具有正变构GABA-A受体神经调节特性的别孕烯醇酮的合成。在HE脑中别孕烯醇酮浓度增加高达7倍。米诺环素减弱小胶质细胞活化可延迟肝性脑病的发生，并可预防肝衰竭时的脑水肿。轻度低温同样有益于急性肝衰竭，导致细胞外脑谷氨酸正常化，并预防实验动物因缺血性或中毒性肝损伤引起的HE的氧化/亚硝化应激。(C)2010爱思唯尔有限公司版权所有。
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of liver failure, characterized neuropathologically by astrocyte swelling, microglial activation and Alzheimer Type II astrocytosis. Molecular studies in HE brain reveal altered expression of genes coding for key astroglial proteins including early losses of expression of GFAP and the glutamate transporter EEAT-2 with concomitant increases of the astrocytic/microglial mitochondrial benzodiazepine receptor (MBR). Decreased expression of EAAT-2 results in decreased glutamate transport and impaired cycling of glutamate-glutamine between astrocytes and neurons, as well as increased extracellular glutamate, activation of the NMDA receptor-mediated cGMP-NO signal transduction pathway, and nitration of tyrosine residues on key astroglial proteins such as glutamine synthetase (GS) and the MBR. GS is uniquely responsible for the removal of excess ammonia in brain. Ammonia-induced activation of MBR in astrocytes and/or microglia results in stimulation of the synthesis of neurosteroids such as allopregnanolone with positive allosteric GABA-A receptor neuromodulatory properties. Allopregnanolone concentrations are increased up to 7-fold in HE brain. Attenuation of microglial activation by minocycline results in a delay in onset of HE and prevents brain edema in liver failure. Mild hypothermia is likewise beneficial in acute liver failure resulting in normalization of extracellular brain glutamate and prevention of oxidative/nitrosative stress in experimental animals with HE resulting from either ischemic or toxic liver injuries. (C) 2010 Elsevier Ltd. All rights reserved.