欠神発作モデルマウスにおける核内転写調節因子の挙動とGABA<SUB>B</SUB>受容体拮抗薬の抗てんかん作用

Abstract

Pharmacological profiles of generalized absence-like seizures in animal models were studied. Selective GABAB antagonists, CGP 35348 and CGP 46381, suppressed absence seizure behavior and spike and wave discharges (SWDs) in lethargic (1h/1h) and γ-butyrolactone (GBL)-treated mice but not in stargazer (stg/stg) mice. Administration of GBL increased nuclear CRE- and AP-1 DNA-binding activities in mouse whole brain. CGP 35348 suppressed the increases in DNA-binding activities. It has been shown that the cortical and thalamic circuitry plays an important role in the genesis and spreading of absence seizures. Gel-shift assays in various brain regions revealed that administration of GBL increased nuclear CRE- and AP-1 DNA-binding activities significantly in the thalamus + midbrain and cerebral cortex but not in the hippocampus, cerebellum or pons-medulla. The region-specific increases in nuclear DNA-binding activities were also suppressed by CGP 35348. These results suggest that GABAB receptors play a significant role in generalized absence seizures in lethargic and GBL-treated mice and that the increases in nuclear CRE- and AP-1 DNA-binding activities are correlated with the GBL-induced absence seizures. It is also suggested that different mechanisms are involved in absence seizures in stargazer mice.