Evaluation of CPP, a selective NMDA antagonist, in various rodent models of epilepsy. Comparison with other NMDA antagonists, and with diazepam and phenobarbital

Abstract

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a novel antagonist at the N-methyl-D-aspartate (NMDA)-preferring subtype of excitatory amino acid receptor, was evaluated in four rodent models of epilepsy, i.e. maximal electroshock seizures and pentylenetetrazol (PTZ)-induced seizures in mice, epileptic gerbils and amygdala-kindled rats. The effect of CPP after systemic (i.p.) injection was compared with that of the clinical antiepileptics, phenobarbital and diazepam, and in gerbils, in addition, with the effect of the NMDA antagonist 2-amino-5-phosphonopentanoate (AP5) and 2-amino-7-phosphonoheptanoate (AP7). CPP, 5 mg/kg i.p., increased the threshold for tonic electroshock seizures but this effect was associated with motor impairment in the chimney test whereas phenobarbital had comparable anticonvulsant potency without motor impairment. The threshold for clonic PTZ seizures was increased by CPP only at high doses (20 mg/kg) which induced ataxia and marked motor impairment in the chimney test, whereas both diazepam and phenobarbital were active in this test at doses which exerted no side-effects. CPP, 2-20 mg/kg i.p., could not reduce the severity or duration of focal and generalized clonic seizures or the duration of amygdalar afterdischarges in the amygdala-kindling model in rats but instead caused ataxia and reduced muscle tone at the higher doses examined. Diazepam and phenobarbital both had anticonvulsant efficacy in this model. CPP at doses of 5-10 mg/kg did not reduce seizure severity in gerbils in which generalized tonic-clonic seizures were induced by air-blast stimulation, but, as in mice and rats, it caused motor impairment.(ABSTRACT TRUNCATED AT 250 WORDS)