REVERSAL OF THE BEHAVIORAL AND ELECTROPHYSIOLOGICAL ABNORMALITIES OF AN ANIMAL-MODEL OF HEPATIC-ENCEPHALOPATHY BY BENZODIAZEPINE RECEPTOR LIGANDS
REVERSAL OF THE BEHAVIORAL AND ELECTROPHYSIOLOGICAL ABNORMALITIES OF AN ANIMAL-MODEL OF HEPATIC-ENCEPHALOPATHY BY BENZODIAZEPINE RECEPTOR LIGANDS
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DOI：
10.1002/hep.1840110307
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发表时间：
1990-03-01
期刊：
影响因子：
13.5
通讯作者：
JONES, EA
中科院分区：
文献类型：
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作者：
GAMMAL, SH;BASILE, AS;JONES, EA
行为和电生理证据表明GABA-苯二氮卓类受体复合物在肝性脑病的发病机制中的作用是通过改良硫代乙酰胺诱导的暴发性肝衰竭引起的肝性脑病大鼠模型获得的。在给予硫代乙酰胺和支持性治疗后，大鼠出现急性肝细胞衰竭，这是由于大面积肝细胞坏死，无肾衰竭或低血糖的证据。在这个模型中肝性脑病的发展是足够缓慢的，容易允许分期的综合征。脑病的突出特征包括旷场活动的标记减少和异常的视觉诱发反应。苯二氮卓受体配体氟马西尼或Ro 15-4513给药后，III至IV期肝性脑病大鼠的自发运动功能缺陷和视觉诱发反应异常均显著改善。氟马西尼或Ro 15-4513的剂量。在肝性脑病大鼠中产生这些效应的氟马西尼或Ro 15-4513剂量对正常大鼠的行为或视觉诱发反应均没有可检测到的作用。苯二氮卓受体配体改善硫代乙酰胺诱导的大鼠模型中与肝性脑病相关的行为抑郁和视觉诱发反应异常的能力表明GABA/苯二氮卓受体复合物参与肝性脑病的发病机制。此外，这些观察结果与半乳糖胺诱导的暴发性肝功能衰竭引起的肝性脑病家兔的观察结果相似，这与以下假设相一致：这两种不同模型中的肝性脑病机制具有共同的最终途径，即通过苯二氮卓类受体的GABA能张力变构增强。这些观察结果表明，苯二氮卓类受体具有激动剂特性的配体浓度增加或可用性增加可能参与肝性脑病的发病机制，苯二氮卓类受体拮抗剂的给药可能对人类肝性脑病的治疗有价值。
Behavioral and electrophysiological evidence implicating the GABA-benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy was obtained using an improved rat model of hepatic encephalopathy caused by thioacetamide-induced fulminant hepatic failure. After the administration of thioacetamide together with supportive therapy, acute hepatocellular failure developed in rats as a result of massive hepatocellular necrosis without evidence of renal failure or hypoglycemia. The evolution of hepatic encephalopathy in this model was sufficiently slow to readily permit the staging of the syndrome. Prominent features of the encephalopathy include a marker reduction in open field activity and an abnormal visual evoked response. Both the deficits in spontaneous motor function and visual evoked response abnormalities of rats in stages III to IV hepatic encephalopathy were significantly improved after the administration of the benzodiazepine receptor ligands flumazenil or Ro 15-4513. Doses of flumazenil or Ro 15-4513. Doses of flumazenil or Ro 15-4513 that produced these effects in rats with hepatic encephalopathy had no detectable action on either the behavior or the visual evoked responses of normal rats. The ability of benzodiazepine receptor ligands to ameliorate both the behavioral depression and the visual evoked response abnormalities associated with hepatic encephalopathy in the thioacetamide-induced rat model suggest an involvement of the GABA/benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy. Inaddition, the similarity of htese observations to those in rabbits with hepatic encephalopathy caued by galactosamine-induced fulminant hepatic failure in compatible with the hypothesis that the mechanisms of hepatic encephalopathy in these two distinct models share a common final pathway, the allosteric enhancement of GABAergic tone through the benzodiazepine recpetor. These observations suggest that increased concentrations or availability of a ligand with agonist properties at the benzodiazepine receptor may be involved in the pathogenesis of hepatic encephalopathy and that administration of benzodiazepine receptor antagonists may be of value in the management of hepatic encephalopathy in man.