STUDIES OF RELATING TO THE PATHOGENESIS OF HEPATIC ENCEPHALOPATHY

由于FHF导致HE的兔和大鼠表现出对 荷包牡丹碱（GABA受体拮抗剂）的惊厥作用， 3-巯基丙酸（GABA合成的抑制剂）。 HE的临床和电生理（VER波形）改善， 苯二氮卓类（BZ）受体可诱导FHF动物 对手。此外，浦肯野神经元的体外自发活动 由于FHF，HE组家兔对抑郁的敏感性增加 GABA/BZ受体复合物的激动剂，包括BZ，和， 与对照神经元相比，当暴露于BZ时， 受体拮抗剂。此外，BZ受体拮抗剂逆转了 HE兔神经元对GABA激动剂抑制超敏反应。的 GAB/VBZ受体复合物的氯离子载体的功能状态 在由FHF引起的HE大鼠模型中显示正常。放射配 放射自显影法测定，与BZ受体的结合减少， 从兔脑中取出未清洗的薄切片。纯化及 HE大鼠脑提取物的表征揭示了存在 可逆的、竞争性的、热和蛋白酶稳定的BZ受体配体， 激动剂性质。这些配体中的两个已被化学表征 1，4 BZ地西泮和N-去甲基地西泮。的浓度 这些化合物在HE大鼠脑中比对照脑中高2-9倍。 总的来说，这些发现表明，在由于FHF引起的HE中：（i）存在 增加GABA能张力;（ii）阻断BZ受体可改善 （iii）BZ受体拮抗剂可能对HE的治疗有价值; （iv）内源性BZ受体激动剂可能与HE有关。

Rabbits and rats with HE due to FHF exhibit increased resistance to the convulsive effects of bicuculline (a GABA receptor antagonist) and 3-mercaptopropionic acid (an inhibitor of GABA synthesis), respectively. Both clinical and electrophysiologic (VER waveform) ameliorations of HE, have been induced in animals with FHF by benzodiazepine (BZ) receptor antagonists. 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 GAB/VBZ 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, heat and protease stable 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.