Methionine sulfoximine epileptogeny and related metabolic changes in the brain of rodents

A glucose hypometabolism was observed in men who suffered of temporal lobe epilepsy and a glucose derivative is utilized in clinics to localize epilep tic foci. However, the relationship between electric discharges leading to epileptic behaviour and the impairment of the brain carbohydrate metabolism is not yet established. Using an experimental model of epilepsy obtained b y the administration of methionine sulfoximine, we try to explain in this w ork the cellular and molecular targets of the covulsant. Despite the large range of epileptogenic activity of methionine sulfoximine in animals, we sh owed that the profile of the seizures depends on animal strains, thus showi ng a possible involvement of genes in its action. Methionine sulfoximine is known for its glycogenic action in animals. We have already shown that it increases the activity and the amount of the key gluconeogenic enzyme fruct ose-1,6-bisphosphatase (EC 3.1.3.11) and its mRNAs. This has been observed in vivo as well as in cultured astrocytes. Since this increase was not para llel to a notable change in the activity of the key glycolytic enzyme phosp hofructokinase (EC 2.7.1.11) which catalyses the reverse reaction of that c atalysed by fructose-l,6-bisphosphatase. there may be changes in the concen trations of metabolites related to these two enzymes:;. So, seven metabolit es related to these two enzymes were measured in the brain of mice submitte d to methionine sulfoximine. There were no significant changes in these met abolite contents during preconvulsive, convulsive, and postconvulsive perio ds. These observations show that the metabolites, principally fructose-6-ph osphate, may be withdrawn by other metabolic pathways, probably. that of gl ycogen synthesis. We concluded that the convulsant may have astrocytes as d irect target cells for the changes observed in carbohydrate metabolism and neurons for changes observed in neurotransmitter levels, principally a decr ease ill dopamine and serotonin levels. This action is different of our pre vious hypothesized action. Whether or not cooperation exists between these two targets has to be demonstrated.