STUDIES OF RELATING TO THE PATHOGENESIS OF HEPATIC ENCEPHALOPATHY

肝性脑病发病机制的相关研究

• 批准号: 3918247
• 负责人: E ANTHONY JONES
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3918247
• 关键词: GABA receptor; acute disease /disorder; aminoacid inhibitor; benzodiazepine receptor; benzodiazepines; bicuculline; brain metabolism; disease /disorder model; drug interactions; evoked potentials; gamma aminobutyrate; heart Purkinje's fiber; hepatic coma /encephalopathy; hepatotoxin; human subject; human tissue; laboratory rabbit; liver disorder chemotherapy; liver failure; liver metabolism; membrane permeability; neuropharmacology; neurotoxins

The abnormal pattern of visual evoked responses (VERs) in animals with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembles that associated with encephalopathy induced by drugs which promote GABA-ergic neurotransmission, including benzodiazepines (BZs). These findings suggest that the pattern of neuronal activity in HE may resemble that associated with activation of the GABA inhibitory neurotransmitter system. Furthermore, rabbits with HE due to FHF exhibit increased resistance to the convulsive effects of the GABA receptor antagonist, bicuculline. Ameliorations of HE (both clinical and electrophysiologic (VER waveform)) have been induced in animals with FHF by 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. 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) An endogenous BZ receptor agonist may contribute to HE. Such a ligand is being isolated from supernatants of brain obtained from models of HE.

动物视觉诱发反应的异常模式 暴发性肝衰竭所致的肝性脑病 (FHF)类似于由以下因素引起的脑病 促进GABA能神经传递的药物，包括 苯二氮卓类(BZS)。这些发现表明， HE患者的神经元活动可能类似于 激活GABA抑制性神经递质系统。 此外，由于FHF导致的HE兔表现出增加 对GABA受体惊厥效应的抵抗 拮抗剂荷包牡丹碱。对HE的改善(包括临床和 电生理(VER波形)已在动物中诱导 用BZ受体拮抗剂治疗FHF。此外，自发进入 家兔浦肯野神经元对FHF致HE的体外活性 通过激动剂表现出对抑郁的更高敏感性 GABA/BZ受体复合体，包括BZ，与 对照神经元在暴露于BZ受体时表现出兴奋 对抗者。这些发现提示FHF所致的HE：(I) GABA能神经递质增加；(Ii)阻断BZ受体 可以改善HE；(Iii)BZ受体拮抗剂可能有价值 (Iv)内源性BZ受体激动剂 可能会对他有所贡献。这样一种配体正被从 取HE模型脑组织上清液。