Abstracts

RATIONALE: Disturbance of glutamatergic neurotransmission probably contribute to epilepsy and neurodegenerative disorders. Augmentation of glutamate uptake would be a therapeutic strategy in such conditions. We therefore investigated whether sodium valproate (VPA) might stimulate glutamate uptake.
METHODS: Male adult Wistar rats were fed perorally through a gastric tube with VPA, 200 (n=7) or 400 (n=8) mg/kg, or control (n=8) mixture twice daily for 90 days. In addition, acute experiments with 400 (n=6) or 800 (n=6) mg/kg i.p. were performed. Glutamate uptake was assessed by uptake of [3H]glutamate into artificial proteoliposomes, while the levels of EAAT1, EAAT2, glial fibrillary acidic protein and synapsin 1 were determined by immunoblotting. Further, the levels of different amino acids and enzyme activities were measured.
RESULTS: Glutamate uptake was dose-dependently increased in the hippocampus, but not in frontal or parietal cortices or in cerebellum. Only in the hippocampus was there a corresponding increase in the glial glutamate transporters EAAT1 and EAAT2. VPA treatment did probably not lead to astrocytosis, since the levels of glial fibrillary acidic protein and glutamine synthetase remained at control level, nor was there increased synaptogenesis, since the levels of synapsin 1 and glutaminase were reduced by high-dose VPA. Acute administration of VPA did not affect glutamate uptake.
CONCLUSIONS: This study shows that hippocampal glutamate uptake may be augmented pharmacologically, and suggests that improvement of glutamate removal may be an important mechanism of action of VPA. The findings also suggests possible differences between acute and chronic effects of antiepileptic drugs.
Support: University of Oslo, Norway and Norwegian Defence Research Establishment, Kjeller, Norway.