Zeneroli M L
J Hepatol. 1985;1(3):301-11. doi: 10.1016/s0168-8278(85)80057-x.
A new approach to pathogenetic study of hepatic encephalopathy was recently undertaken in order to identify the neurological alterations of the brain which characterize the coma. In this study attention was firstly addressed to a correct and objective evaluation of the comatose state in rats with fulminant hepatic failure induced by galactosamine. For this purpose visual evoked potentials were utilized since this electrophysiological test proved reliable and sensitive on the basis of an extensive pharmacological study. Two different stages of coma were identified in the rat and they were named mild and severe. Receptor binding studies performed on brain membranes of these rats show in the mild stage an increased number of low and high affinity GABA receptors and a decreased affinity of dopamine receptors. The severe stage is characterized by the persistence of only high affinity GABA receptors and a reduced number of dopamine receptors. This imbalance between inhibitory and excitatory receptor systems may explain the generalized central nervous system depression which characterizes the hepatic encephalopathy while the increased number of benzodiazepine receptors found in both stages of coma may account for the brain supersensitivity to sedative administration of patients with liver disease and for the sedative-induced episodes of coma. These receptor alterations may be attributed to a disuse and/or a partial degeneration of nerve terminals due to peripheral neurotoxins (i.e., ammonia, mercaptans, short chain fatty acids) and the decrease of glutamate decarboxylase activity and of zinc levels in brain tissues seems to be respectively a direct and an indirect demonstration of this phenomenon. Bearing in mind the supersensitivity of the GABA-benzodiazepine receptor system and their reciprocal interaction, a benzodiazepine antagonist was administered to rats in mild stage of encephalopathy. Electrophysiological and benzodiazepine binding studies demonstrated that this treatment can temporarily counteract some of the neurological disturbances of the earlier stage of coma and act as antidote of the sedative-induced episodes of coma.
最近，人们采用了一种新的肝性脑病发病机制研究方法，以确定导致昏迷的大脑神经学改变。在这项研究中，首先关注的是对由半乳糖胺诱导的暴发性肝衰竭大鼠昏迷状态进行正确、客观的评估。为此，使用了视觉诱发电位，因为基于广泛的药理学研究，这种电生理测试被证明是可靠且敏感的。在大鼠中确定了两个不同的昏迷阶段，分别称为轻度和重度。对这些大鼠的脑膜进行的受体结合研究表明，在轻度阶段，低亲和力和高亲和力γ-氨基丁酸（GABA）受体数量增加，多巴胺受体亲和力降低。重度阶段的特征是仅存在高亲和力GABA受体，多巴胺受体数量减少。抑制性和兴奋性受体系统之间的这种失衡可能解释了肝性脑病所特有的中枢神经系统普遍抑制，而在昏迷的两个阶段中发现的苯二氮䓬受体数量增加，可能解释了肝病患者对镇静剂给药的大脑超敏反应以及镇静剂诱发的昏迷发作。这些受体改变可能归因于外周神经毒素（即氨、硫醇、短链脂肪酸）导致的神经末梢废用和/或部分退化，脑组织中谷氨酸脱羧酶活性降低和锌水平降低似乎分别是这一现象的直接和间接证明。考虑到GABA-苯二氮䓬受体系统的超敏性及其相互作用，在肝性脑病轻度阶段的大鼠中给予了苯二氮䓬拮抗剂。电生理和苯二氮䓬结合研究表明，这种治疗可以暂时抵消昏迷早期的一些神经功能障碍，并作为镇静剂诱发的昏迷发作的解毒剂。
