Gammal S H, Basile A S, Geller D, Skolnick P, Jones E A
Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
Hepatology. 1990 Mar;11(3):371-8. doi: 10.1002/hep.1840110307.
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 marked 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 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. In addition, the similarity of these observations to those in rabbits with hepatic encephalopathy caused by galactosamine-induced fulminant hepatic failure is 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 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
使用硫代乙酰胺诱导暴发性肝衰竭所致肝性脑病的改良大鼠模型，获得了行为学和电生理学证据，表明γ-氨基丁酸-苯二氮䓬受体复合物与肝性脑病的发病机制有关。给予硫代乙酰胺并辅以支持治疗后，大鼠因大量肝细胞坏死而出现急性肝细胞衰竭，无肾衰竭或低血糖证据。该模型中肝性脑病的进展足够缓慢，便于对该综合征进行分期。脑病的突出特征包括旷场活动显著减少和视觉诱发电位异常。给予苯二氮䓬受体配体氟马西尼或Ro 15-4513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电位异常均得到显著改善。在肝性脑病大鼠中产生这些作用的氟马西尼或Ro 15-4513剂量，对正常大鼠的行为或视觉诱发电位均无明显作用。在硫代乙酰胺诱导的大鼠模型中，苯二氮䓬受体配体能够改善与肝性脑病相关的行为抑制和视觉诱发电位异常，提示γ-氨基丁酸/苯二氮䓬受体复合物参与了肝性脑病的发病机制。此外，这些观察结果与半乳糖胺诱导暴发性肝衰竭所致肝性脑病兔的观察结果相似，这与以下假设相符：这两种不同模型中肝性脑病的机制共享一个共同的最终途径，即通过苯二氮䓬受体变构增强γ-氨基丁酸能张力。（摘要截短于250字）
