Ishige K, Aizawa M, Ito Y, Fukuda H
Department of Pharmacology, College of Pharmacy, Nihon University, Chiba, Japan.
Neuropharmacology. 1996 Jan;35(1):45-55. doi: 10.1016/0028-3908(95)00176-x.
We examined the involvement of the GABAB receptor and the coordinated induction of nuclear transcriptional factors in experimental generalized absence seizures induced by gamma-butyrolactone (GBL) in mice. Although administration of GBL 50 mg/kg did not show any effects on behavior or ECoG pattern, higher doses of GBL (70 and 100 mg/kg, i.p.) induced behavioral changes associated with 3-6-Hz spike and wave discharges in the mice. CGP 35348, a GABAB receptor antagonist, suppressed both the GBL-induced absence seizures and the spike and wave discharges. The antiepileptic effects of CGP 35348 (200 mg/kg, i.p.) were stronger than those of ethosuximide (200 mg/kg, i.p.). Sodium valproate (100 mg/kg, i.p.) attenuated the early phase but not the late phase of the GBL-induced absence seizures. Gel-mobility assay demonstrated that administration of an effective dose of GBL for eliciting spike and wave discharges dose-dependently increased nuclear cyclic AMP-responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in mouse whole brain. The increases in nuclear CRE- and AP-1 DNA-binding were antagonized by CGP 35348 in a dose-dependent fashion. In addition, GABAB receptor binding assay revealed that GBL or antiepileptic drugs did not displace [3H]baclofen binding in cerebral cortical membranes. In contrast, gamma-hydroxybutyrate (GHB), an active metabolite of GBL, inhibited [3H]baclofen binding in a concentration-dependent manner. These results suggest that GABAB receptor-mediated synaptic responses are involved in GBL-induced generalized absence seizures and that the increases in nuclear CRE- and AP-1 DNA-binding activities are correlated with the GBL-induced generalized absence seizures.
我们研究了γ-丁内酯（GBL）诱导的小鼠实验性全身性失神发作中GABAB受体的参与情况以及核转录因子的协同诱导作用。虽然给予50mg/kg的GBL对行为或脑电图模式没有任何影响，但更高剂量的GBL（70和100mg/kg，腹腔注射）会在小鼠中诱导与3 - 6Hz棘波和慢波放电相关的行为变化。GABAB受体拮抗剂CGP 35348可抑制GBL诱导的失神发作以及棘波和慢波放电。CGP 35348（200mg/kg，腹腔注射）的抗癫痫作用强于乙琥胺（200mg/kg，腹腔注射）。丙戊酸钠（100mg/kg，腹腔注射）可减弱GBL诱导的失神发作的早期阶段，但对晚期阶段无效。凝胶迁移试验表明，给予有效剂量的GBL以引发棘波和慢波放电可剂量依赖性地增加小鼠全脑细胞核环磷酸腺苷反应元件（CRE）和激活蛋白1（AP - 1）的DNA结合活性。CGP 35348以剂量依赖性方式拮抗细胞核CRE和AP - 1 DNA结合的增加。此外，GABAB受体结合试验表明，GBL或抗癫痫药物不会取代大脑皮质膜中[3H]巴氯芬的结合。相反，GBL的活性代谢产物γ-羟基丁酸（GHB）以浓度依赖性方式抑制[3H]巴氯芬的结合。这些结果表明，GABAB受体介导的突触反应参与了GBL诱导的全身性失神发作，并且细胞核CRE和AP - 1 DNA结合活性的增加与GBL诱导的全身性失神发作相关。
