[Metabotropic glutamate receptors as a possible target of antiepileptic therapy]. / Metabotropní glutamátové receptory jako mozný cíl antiepileptické terapie.

Antagonists of glutamate ionotropic receptors exhibit marked anticonvulsant action but also serious side effects, therefore attention is shifted to drugs influencing metabotropic glutamate receptors. These receptors are classified into three groups (I-III) and eight subtypes. Anticonvulsant action in experimental models was demonstrated for antagonists of group I receptors (mGluR1 and mGluR5) as well as for agonists of groups II (mGluR2 and mGluR3) and III (mGluR4, mGluR6, mGluR7 and mGluR8). Preclinical data are far from being complete but clear anticonvulsant action and absence of serious side effects speak in favor of further research.

Different effects of nonNMDA and NMDA receptor antagonists (NBQX and dizocilpine) on cortical epileptic afterdischarges in rats.

Excitatory amino acids play an important role in generation of epileptic seizures. To study the participation of different types of their receptors in cortical epileptic afterdischarges, a noncompetitive NMDA receptor antagonist dizocilpine and a competitive AMPA receptor antagonist NBQX were used. Adult rats with implanted epidural stimulation and registration electrodes were pretreated either with NBQX (30 or 60 mg/kg i.p.) or with dizocilpine (0.1 or 0.5 mg/kg i.p.) and low-frequency stimulation of sensorimotor cortical area was repeatedly applied with stepwise increased current intensities. Lower dose of NBQX unexpectedly decreased thresholds for elicitation of spike-and-wave afterdischarges (ADs), clonic seizures accompanying this type of ADs and for transition into the second, limbic type of ADs. Lower dose of dizocilpine increased these three thresholds. Higher doses of either drug did not significantly change threshold intensities. Duration of ADs was also influenced by the two antagonists in opposite directions: higher dose of NBQX resulted in prolongation of ADs mainly due to an increased duration of the spike-and-wave part of ADs whereas dizocilpine shortened ADs in a dose-dependent manner affecting both types of ADs. In addition, NBQX did not influence interhemispheric responses meanwhile dizocilpine moderately suppressed these evoked potentials. According to our results, NMDA receptors are important for generation of cortical epileptic afterdischarges meanwhile the role of AMPA receptors is not clear and has to be analyzed.

Anticonvulsant action of an antagonist of metabotropic glutamate receptors mGluR5 MPEP in immature rats.

Antagonists of type I of metabotropic glutamate receptors exhibit anticonvulsant action in adult as well as immature rodents. To know the anticonvulsant profile of a specific mGluR5 antagonist MPEP in developing rats, two models of epileptic seizures were used. MPEP (10, 20 or 40 mg/kg i.p.) suppressed in a dose-dependent manner epileptic afterdischarges induced by electrical stimulation of sensorimotor cortical area in three age groups (12, 18 and 25 days old). The anticonvulsant action was more expressed in the youngest group than in older animals so that in 25-day-old rats an additional dose of 80 mg/kg was used. In contrast to this marked anticonvulsant action, MPEP at a dose of 40 mg/kg i.p. in 18-day-old rat pups and at doses of 40 and 80 mg/kg in 25-day-old rat pups did not affect episodes of spike-and-wave rhythm elicited by low doses of pentetrazol. Our results delineate the profile of the anticonvulsant action of MPEP and confirm the higher efficacy of this antagonist at early developmental stages in comparison with prepubertal animals.