STUDIES RELATING TO THE PATHOGENESIS OF HEPATIC ENCEPHALOPATHY & HEPATIC FAILURE

临床和电生理(VER波形)的改善 肝性脑病(HE)已在FHF动物中被诱发 具有拮抗剂性质的苯二氮卓(BZ)受体配体。 此外，自发性浦肯野神经元的体外活动。 FHF所致的HE兔对抑郁的敏感性增加 由GABA/BZ受体复合体的激动剂，包括BZ，和，在 与对照组相比，暴露于BZ时表现出兴奋 受体拮抗剂。此外，一种BZ受体拮抗剂逆转了 HE兔神经元对GABA激动剂抑制的超敏反应。 GABA/BZ受体氯离子载体的功能状态 在FHF的大鼠HE模型中，复合体被证明是正常的。 放射自显影测定与BZ受体结合的放射性配基， 在HE兔脑中未清洗的薄片中呈下降趋势。 HE大鼠脑提取液的纯化和性质研究表明 可逆的、竞争性的BZ受体配体与激动剂的存在 属性。其中两个配体的化学特征是 1，4-BZS安定和N-脱甲基安定。三种物质的浓度 这些化合物在HE大鼠脑中的含量是对照组的2-9倍 大脑。总体而言，这些发现表明，由于FHF，在HE中：(I)有 增加GABA能张力；(Ii)阻断BZ受体可以 改善HE；(Iii)BZ受体拮抗剂可能在 可能是内源性BZ受体激动剂 为他做贡献。BZ受体配体改善肝性脑病的疗效 在动物模型中似乎并不依赖于它们的内在活动， 但可能与它们对BZ受体亚型的亲和力有关 除了对安定敏感的受体。

Both clinical and electrophysiologic (VER waveform) ameliorations of hepatic encephalopathy (HE) have been induced in animals with FHF by benzodiazepine (BZ) receptor ligands with antagonist properties. Furthermore, spontaneous in vitro activity of Purkinje neurons from rabbits in HE due to FHF exhibited increased sensitivity to depression by agonists of the GABA/BZ receptor complex, including a BZ, and, in contrast to control neurons, exhibited excitation when exposed to BZ receptor antagonists. In addition, a BZ receptor antagonist reversed the hypersensitivity of HE rabbit neurons to depression by a GABA agonist. The functional status of the chloride ionophore of the GABA/BZ receptor complex has been shown to be normal in a rat model of HE due to FHF. Radioligand binding to BZ receptors, determined autoradiographically, was decreased in thin unwashed sections from HE rabbit brains. Purification and characterization of HE rat brain extracts revealed the presence of reversible, competitive, BZ receptor ligands with agonist properties. Two of these ligands have been chemically characterized as the 1,4-BZs diazepam and N-desmethyldiazepam. The concentrations of these compounds were 2-9 fold greater in HE rat brain than control brain. Overall, these findings suggest that in HE due to FHF: (i) There is increased GABA -ergic tone; (ii) Blockading of BZ receptors can ameliorate HE; (iii) BZ receptor antagonists may be of value in the management of HE; and (iv) Endogenous BZ receptor agonists probably contribute to HE. The efficacy of BZ receptor ligands in ameliorating HE in animal models does not appear to depend on their intrinsic activity, but may be related to their affinity for BZ receptor subtypes in addition to the diazepam sensitive receptor.