Attenuation of seizures induced by homocysteic acid in immature rats by metabotropic glutamate group II and group III receptor agonists

Abstract

Previous studies demonstrated that selected agonists for metabotropic glutamate group II and group III receptors can provide protection against seizures in adult animals. The present study has examined the potential effect of some of these compounds on seizures induced in immature rats by intracerebroventricular infusion of dl-homocysteic acid ( dl-HCA, 600 nmol/side). Rat pups were sacrificed during generalised clonic–tonic seizures, 50–60 min after infusion. Comparable time intervals were used for sacrificing the pups which had received the protective drugs. The anticonvulsant effect was evaluated according to the suppression of behavioural manifestations of seizures and the protection of energy metabolite changes which normally accompany these seizures (large decreases of glucose and glycogen, and ∼7- to 10-fold accumulation of lactate). Partial protection was exhibited by group II mGluR agonist (2 S,2′ R,3′ R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG IV, 0.6 nmol) and this effect was abolished after pretreatment with an antagonist for group II mGluRs ( RS)-α-methyl-4-tetrazolylphenylglycine (MTPG, 100 nmol). In high doses (5–100 nmol), however, DCG IV evoked seizures which were prevented by AP7, suggesting that the convulsant effect was mediated by interaction with NMDA receptors. A pronounced anticonvulsant effect against dl-HCA-induced seizures was achieved with low doses of a highly selective group II mGluR agonist (2 R,4 R)-4-aminopyrrolidine-2,4-dicarboxylate (2 R,4 R-APDC, 0.6 nmol), group II agonist and group I mGluR antagonist ( S)-4-carboxy-3-hydroxyphenylglycine (( S)-4-C3HPG, 0.6 nmol) and group III mGluR agonist ( RS)-1-amino-3-(phosphonomethylene) cyclobutane-carboxylic acid (32 nmol). Generalised clonic–tonic seizures were completely suppressed and the metabolic changes were markedly ameliorated, there being only a 1.5-, 2- and 2.5-fold rise of lactate, respectively. Higher doses of ( S)-4-C3HPG (1–100 nmol) were, however, less anticonvulsant than low doses. The present results have confirmed that mGluRs may be considered a potential target for treatment of epilepsy.