The present study has examined the
anticonvulsant and
neuroprotective effect of group II
metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the model of
seizures induced in immature 12-day-old rats by bilateral
intracerebroventricular infusion of
dl-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-
tonic seizures, approximately 45-50 min after infusion. Comparable time intervals were used for sacrificing the pups which had received
2R,4R-APDC. Low doses of
2R,4R-APDC (0.05 nmol/side) provided a pronounced
anticonvulsant effect which was abolished by pretreatment with a selective group II mGluR antagonist
LY341495. Generalized clonic-
tonic seizures were completely suppressed and cortical energy metabolite changes which normally accompany these
seizures were either normalized (decrease of
glucose and
glycogen) or markedly reduced (an accumulation of
lactate). EEG recordings support the marked
anticonvulsant effect of
2R,4R-APDC, nevertheless, this was only partial. In spite of the absence of obvious motor phenomena, isolated spikes or even short periods of partial ictal activity could be observed. Isolated spikes could also be seen in some animals after application of
2R,4R-APDC alone, reflecting most likely subclinical proconvulsant activity of this agonist. The
neuroprotective effect of
2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced
seizures. Massive neuronal degeneration, as revealed by
Fluoro-Jade B staining, was observed in a number of brain regions following infusion of DL-HCA alone (seizure group), whereas
2R,4R-APDC pretreatment provided substantial neuroprotection. The present findings support the possibility that group II mGluRs are a promising target for a novel approach to treating
epilepsy.