STUDIES OF THE PATHOGENESIS OF ACUTE HEPATIC COMA

兔视诱发电位异常模式的实验研究 暴发性肝衰竭所致的肝性脑病 类似于巴比妥酸盐引起的昏迷，一种 苯二氮卓类或γ-氨基丁酸(GABA)激动剂。就像这些 药物通过与神经细胞上的结合部位相互作用而引起神经抑制。 突触后神经膜上的GABA受体复合体，这些发现 提示HE患者的神经元活动模式可能类似于 与GABA抑制性神经递质的激活有关 系统。在中枢神经系统之外，GABA的主要来源是肠道细菌和 其分解代谢的主要部位是肝脏。在兔体内诱发FHF时 在肝性脑病发病之前，血浆中的 GABA和血脑通透性的非特异性增加 对GABA非代谢异构体的屏障(BBB)。要考虑到 GABA的快速代谢是一种改进的Oldendorf技术，该技术采用了 血管标记物的使用，已经被用来证明大脑 HE组GABA摄取指数升高。流行性出血热与 脑内受体密度的显著增加 抑制性氨基酸神经递质，GABA和甘氨酸，以及 苯二氮卓类(BZ)。FHF也与显著的下降有关 兴奋性氨基酸的大脑受体密度 神经递质谷氨酸和天冬氨酸。与FHF无关 四种非氨基酸的大脑受体密度的任何变化 神经递质。这些发现表明，当肝脏衰竭时：(I) 肝脏GABA代谢受损导致 肠道来源的血浆中的GABA，(Ii)血浆GABA进入大脑 通过通透性的血脑屏障，有助于抑制HE和 (Iii)大脑对兴奋性氨基酸可能不那么敏感 神经递质和对抑制性氨基酸更敏感 神经递质。BZ或GABA对FHF兔的治疗作用 拮抗剂已被证明可以改善HE(临床和 电生理学)。

The abnormal pattern of visual evoked potentials (VEPs) in rabbits with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembles that associated with coma induced by a barbiturate, a benzodiazepine or a gamma-amino-butyric acid (GABA) agonist. As these drugs induce neural inhibition by interacting with binding sites on the GABA receptor complex on postsynaptic neural membranes, these findings suggest that the pattern of neuronal activity in HE may resemble that associated with the activation of the GABA inhibitory neurotransmitter system. Outside the CNS the main source of GABA is gut bacteria and the main site of its catabolism is the liver. When FHF was induced in rabbits the onset of HE was preceded by a marked increase in the plasma levels of GABA and by a nonspecific increase in the permeability of the blood brain barrier (BBB) to a nonmetabolized isomer of GABA. To take account of the rapid metabolism of GABA a modified Oldendorf technique, which employed the use of a vascular marker, has been used to demonstrate that the brain uptake index for GABA is increased in HE. FHF was associated with significant increases in the densities of brain receptors for the inhibitory amino acid neurotransmitters, GABA and glycine, and for benzodiazepines (BZ). FHF was also associated with significant decreases in the densities of brain receptors for the excitatory amino acid neurotransmitters, glutamate and aspartate. FHF was not associated with any change in the densities of brain receptors for four non-amino acid neurotransmitters. These findings suggest that as the liver fails: (i) impaired hepatic metabolism of GABA contributes to an increase of gut-derived GABA in plasma, (ii) plasma GABA gains access to the brain through a permeable BBB and contributes to the neural inhibition of HE and (iii) the brain may be less sensitive to excitatory amino acid neurotransmitters and more sensitive to inhibitory amino acid neurotransmitters. In rabbits with FHF the administration of a BZ or GABA antagonist has been shown to ameliorate HE (both clinically and electrophysiologically).