Acute and chronic anticonvulsant effects of D(-)CPPene in genetically epilepsy-prone rats

Acute administration (0.4-12 mumol/kg, i.p.) of the NMDA antagonist D(-)CPPene (3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid; molecular weight = 250.2) dose-dependently reduced the incidence of sound-induced clonic seizures in genetically epilepsy-prone (GEP) rats. The ED50 value against clonic seizure at +1 h was 2.6 (2.2-3.2) and at +4 h was 1.7 (1.3-2.3) mumol/kg (i.p.). Twelve hours after chronic administration of an anticonvulsant dose of D(-)CPPene (4 mumol/kg, i.p., twice daily at 09.00 and 21.00 h, for 14 days), repeat administration of D(-)CPPene (1.2-12 mumol/kg, i.p.) gave ED50 values against clonic seizure at +1 h of 3.4 (2.5-4.8) mumol/kg and at +4 h of 2.8 (2.0-3.9) mumol/kg (i.p.). There was no significant difference observed between ED50 values for these acute and chronic groups. The duration of the anticonvulsant effect observed between +1 h and +8 h after D(-)CPPene (0.4-12 mumol/kg, i.p.) was similar in the acute and chronic groups. The ED50 values for D(-)CPPene-induced impairment of locomotor performance (using a rotarod) at +3 h were 6.8 (4.4-10.4) and 6.4 (4.1-10.1) mumol/kg (i.p.) for the acute and chronic groups respectively. At +7 h after D(-)CPPene administration the ED50 value for locomotor impairment was 19.5 (10.6-36.0) mumol/kg (i.p.) in the acute group. In this study there is no evidence of tolerance to the anticonvulsant effects and little evidence of tolerance to the adverse effects (ataxia) of D(-)CPPene in GEPRs.