STUDIES RELATING TO THE PATHOGENESIS OF HEPATIC ENCEPHALOPATHY & HEPATIC FAILURE

肝性脑病发病机制的相关研究

• 批准号: 3840476
• 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/3840476
• 关键词: GABA receptor; aminoacid inhibitor; autoradiography; benzodiazepine receptor; benzodiazepines; bicuculline; brain metabolism; cerebellar Purkinje cell; chloride channels; diazepam; disease /disorder model; electrophysiology; gamma aminobutyrate; hepatic coma /encephalopathy; human tissue; inhibitor /antagonist; ionophores; laboratory rabbit; laboratory rat; ligands; liver failure; neuropharmacology; receptor binding; receptor sensitivity; sectioning; stimulant /agonist

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.

临床和电生理（VER 波形）改善 患有 FHF 的动物可诱发肝性脑病 (HE) 具有拮抗特性的苯二氮卓（BZ）受体配体。 此外，浦肯野神经元的自发体外活动 因 FHF 而患有 HE 的兔子表现出对抑郁症的敏感性增加 通过 GABA/BZ 受体复合物（包括 BZ）的激动剂，并且， 与对照神经元相反，当暴露于 BZ 时表现出兴奋 受体拮抗剂。此外，BZ 受体拮抗剂逆转了 HE 兔神经元对 GABA 激动剂抑制的超敏反应。 GABA/BZ 受体氯离子载体的功能状态 复合物已被证明在 FHF 引起的 HE 大鼠模型中是正常的。 放射自显影测定放射性配体与 BZ 受体的结合， HE 兔大脑未清洗的薄切片中的细胞因子减少。 HE 大鼠脑提取物的纯化和表征揭示了 存在可逆、竞争性 BZ 受体配体和激动剂 特性。其中两个配体的化学特征为 1,4-BZ 地西泮和 N-去甲基地西泮。的浓度 这些化合物在 HE 大鼠大脑中的含量比对照组高 2-9 倍 脑。总体而言，这些研究结果表明，FHF 引起的 HE 中：(i) GABA 能张力增加； (ii) 阻断 BZ 受体可以 改善HE； (iii) BZ 受体拮抗剂可能在以下方面有价值： 高等教育的管理； (iv) 内源性 BZ 受体激动剂可能 为高等教育做出贡献。 BZ 受体配体改善 HE 的功效 在动物模型中似乎并不依赖于它们的内在活性， 但可能与它们对 BZ 受体亚型的亲和力有关 除地西泮敏感受体外。