Abstracts

RATIONALE: To find out if an anticonvulsant action of MPEP, an antagonist of type I of metabotropic glutamate receptors, is present also in immature experimental animals. The anticonvulsant efficacy of this drug was recently proved in adult rodents therefore we studied this action at different stages of postnatal development in rats.
METHODS: Rat pups 12, 18 and 25 days old were pretreated with MPEP (Tocris, an antagonist specific for receptors containing mGluR5, freshly dissolved in isotonic saline in a concentration of 5 mg/ml) in doses of 10, 20, 40, and/or 80 mg/kg i.p. 15 minutes before an injection of pentetrazol (Sigma, St.Louis, MO) in a dose of 100 mg/kg s.c. Controls were pretreated with physiological saline in a volume corresponding to the highest dose of MPEP. Individual age and dose groups were formed by 8-10 rats. Animals were observed for 30 min after pentetrazol administration and the presence, pattern and latencies of minimal clonic and generalized tonic-clonic seizures were recorded. Seizure severity was quantified using a 5-point scale (1-myoclonic jerks, 2-atypical minimal seizures, 3-minimal seizures, 4-generalized seizures without the tonic phase, 5-complete generalized tonic-clonic seizures).
RESULTS: Minimal seizures were not induced in 12-day-old rats even under control conditions whereas all control animals in the two older groups exhibited this type of seizures. A dose-dependent decrease of incidence of minimal seizures was observed in 18-day-old pups, statistical significance was reached with the 40-mg/kg dose. On the contrary, even the 80-mg/kg dose did not result in a significant change of incidence in 25-day-old animals. Incidence of generalized seizures remained unchanged in all three age groups but there was a change in their pattern - the tonic phase was selectively suppressed. This effect was best expressed in the youngest rats (a significant decrease with the 20-mg/kg dose), the dose-effect relationship was clearly seen in the two younger groups. In addition, an increase of latencies of minimal seizures was observed after the highest dose of MPEP in all three age groups, latencies of generalized seizures were prolonged only in 12-day-old rats. A decrease of seizure severity from point 5 to point 4 was again age-dependent, the dose of 10 mg/kg was efficient in the youngest group whereas only the highest dose resulted in a significant change in 25-day-old rats.
CONCLUSIONS: A specific antagonist of type I glutamate metabotropic receptors MPEP exhibited anticonvulsant effects in all age groups studied. There was an age-specific action against minimal seizures (effects in 18-day-old rats only) and a specific suppression of the tonic phase of generalized seizures in all age groups with a developmental shift in the sensitivity demonstrating the highest efficacy of this drug in the youngest animals. Our data demonstrated a possible use of drugs with above mentioned mechanism of action as anticonvulsants even during ontogeny. Possible side effects of drugs influencing metabotropic glutamate receptors have to be studied.
[Supported by: a Center for Neuropsychiatric Studies, project No. LN00B122]; (Disclosure: Honoraria - Speaker for Glaxo Wellcome, Janssen Cilag, Sanofi, Desitin at local meetings in Czech Republic)