cgp-46381 and Epilepsy--Absence

To characterize seizure-associated increases in cerebral cortical and thalamic cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in lethargic (lh/lh) mice, a genetic model of absence seizures, we examined the effects of ethosuximide and CGP 46381 on these DNA-binding activities. Repeated administration (twice a day for 5 days) of ethosuximide (200 mg/kg) or CGP 46381 (60 mg/kg) attenuated both seizure behavior and the increased DNA-binding activities, and was more effective than a single administration of these drugs. These treatments did not affect either normal behavior or basal DNA-binding activities in non-epileptic control (+/+) mice. Gel supershift assays revealed that the increased CRE-binding activity was attributable to activation of the binding activity of CREB, and that the c-Fos-c-Jun complex was a component of the increased AP-1 DNA-binding activity.

Topics: Animals; Anticonvulsants; Cerebellum; Cerebral Cortex; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; DNA; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsy, Absence; Ethosuximide; GABA Antagonists; GABA-B Receptor Antagonists; Hippocampus; Mice; Phosphinic Acids; Sleep Stages; Thalamus; Transcription Factor AP-1; Treatment Outcome

Absence seizures are characterised by a well-defined disturbance of thalamocortical function, and there is no spread to other systems. In this study, we continue our examination of the mechanisms underlying the increased nuclear cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in a gamma-butyrolactone (GBL)-induced mouse model of absence seizure. The administration of GBL increased CRE- and AP-1 DNA-binding activities in the cerebral cortex and thalamus, but not in other regions such as the hippocampus, cerebellum or pons + medulla oblongata, at doses which induced absence seizures. Not only the absence-seizure behavior but also the increased CRE- and AP-1 DNA-binding activities in the thalamocortical regions were reversibly inhibited by ethosuximide, a typical anti-absence drug, and the GABAB antagonists CGP 35348 and CGP 46381. A gel-supershift assay revealed that the GBL-induced CRE-binding activity was supershifted by an anti-CRE-binding protein (CREB) antibody, and that AP-1 DNA-binding activity was blocked by anti-c-Jun and anti-c-Fos antibodies. These results suggest that increased CRE- and AP-1 DNA-binding activities in the cerebral cortex and thalamus are related to the pathogenesis of generalized absence seizures and that these increases in DNA-binding activity are related to ethosuximide- and GABAB antagonist-sensitive abnormal neuronal activity in the thalamocortical circuit.

Topics: 4-Butyrolactone; Activating Transcription Factor 2; Animals; Anticonvulsants; Brain; Brain Chemistry; Cerebral Cortex; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; DNA-Binding Proteins; Epilepsy, Absence; Ethosuximide; GABA Antagonists; Mice; Organophosphorus Compounds; Phosphinic Acids; Thalamus; Transcription Factor AP-1; Transcription Factors