Abstracts

Many antagonists of NMDA receptors exhibit a powerful anticonvulsant action but also strong unwanted side effects. To utilize potential of these drugs attention is now focused on specific NMDA antagonists. We decided to study effects of representants of the two above mentioned classes low-affinity noncompetitive antagonist memantine and NR2B-specific antagonist ifenprodil in immature rats., Two models of epileptic seizures were used [ndash] pentetrazol(PTZ)-induced motor seizures and cortical epileptic afterdischarges (ADs) induced by stimulation of the sensorimotor cortex. Male rats of the Wistar strain 12, 18, and 25 days old were tested. The same age groups were studied behaviorally to find possible side effects. Spontaneous behavior in the open field was registered and motor performance was checked by means of age-specific tests. Memantine was administered intraperitoneally in doses of 10, 20 and 40 mg/kg, ifenprodil in doses of 10, 20 and 40 mg/kg. Each age and dose group in each experiment was formed by 8 to 10 animals., Memantine suppressed generalized tonic-clonic seizures (GTCS) in a dose-dependent manner in all age groups. In contrast, it potentiated minimal clonic seizures. Ifenprodil suppressed only the incidence of the tonic phase of GTCS in 12- and 18-day-old rats.
Memantine increased threshold intensities for elicitation of spike-and-wave type of AD in 12- and 18-day-old rats as well as threshold for the other (mixed) type of ADs (due to a transition of epileptic activity into the limbic system) in 25-day-old rats. Duration of ADs was shortened in all age groups. Ifenprodil pretreatment decreased threshold intensities for elicitation of mixed type of ADs in 18- and 25-day-old rats and increased duration of these ADs in 25-day-old rats. If administered when the animals allready passed repeated ADs, it significantly shortened ADs in 12- and 18- but not 25-day-old animals.All doses of memantine increased locomotor activity in 12- and 18-day-old rats, the change in the oldest group was not significant. The 20- and 40-mg/kg doses impaired motor performance in all age groups. Ifenprodil increased locomotor activity only in 12-day-old rats and motor performance was changed only with the highest dose in 12- and 25-day-old rats. Duration of the impairment of motor performance by either drug was shorter than duration of an anticonvulsant effect., Memantine exhibits anticonvulsant action as well as side effects described for common NMDA atagonists. Ifenprodil has an action mostly in the youngest group what is in agreement with developmenal decrease of NR2B subunits in the NMDA receptors., (Supported by research projects No. LC554 and AV0Z 50110509.)