Efficacy of anticonvulsant substances in the 6Hz seizure test: Comparison of two rodent species.

Usually performed in the mouse, the 6Hz seizure test is used for screening potential new anticonvulsant substances against complex partial seizures. Nevertheless, advanced models of temporal lobe epilepsy (TLE) are more often performed in rats, so that possible species-related differences may complicate the development of anticonvulsant substances. The aim of the present study was to evaluate the feasibility of adapting the 6Hz test in the rat. We first compared the effects of increasing current intensities for inducing seizures in the mouse and in the rat. This step was followed by the evaluation of the activity of anticonvulsant substances. Animals received an electrical stimulation with a constant current via corneal electrodes. The seizure was characterized by the presence of forelimb clonus immediately after stimulation. Spontaneous locomotion was evaluated following the 6Hz test. In the rat, the forelimb seizure score was intensity-dependently increased and seizures were observed in all animals tested at 44mA. In the mouse, the seizures were of lower magnitude and they were not observed in all mice stimulated at 44mA. In both species, levetiracetam (LEV) clearly decreased the forelimb seizure score over the dose-range 100-300mg/kg without affecting locomotion. Valproate (VPA) displayed anticonvulsant activity at 200mg/kg and fully protected both species at 300mg/kg, a dose producing sedative effects in the mouse. Phenytoin (PHT) showed slight to moderate anticonvulsant activity at 100mg/kg in the mouse and at 60 and 100mg/kg in the rat without modifying locomotor activity. Lamotrigine (LTG) partially antagonized forelimb seizure at 60mg/kg in the mouse and at 30-60mg/kg in the rat, but it induced clear motor impairments at high dose in both species. Our data suggest that in the 6Hz test, the magnitude and the nature of seizures differed between the mouse and the rat for a given current intensity. Nevertheless, the pharmacological profile of anticonvulsant substances was similar in both species for the 4 substances tested. Dose-dependent efficacy of LEV and VPA was observed and LTG and PHT also showed anticonvulsant activity, even though the magnitude of the effects remained moderate for these two last substances. The 6Hz test in the rat therefore appears as a useful model which may be performed prior to follow-up models of partial seizures performed in the same species.

Evaluation of pro-convulsant risk in the rat: spontaneous and provoked convulsions.

INTRODUCTION: The aim of the present study was to evaluate the utility of different tests performed in the absence or presence of factors promoting seizures in order to evaluate the pro-convulsant effects of drugs. We studied the effects of theophylline in the rat since this is a well-known pro-convulsant substance in humans. METHODS: The occurrence of spontaneous convulsions following administration of theophylline was evaluated by observation in the Irwin Test and by measuring brain activity using video-EEG recording in conscious telemetered animals. Theophylline was also tested in the electroconvulsive shock (ECS) threshold and pentylenetetrazole (PTZ)-induced convulsions tests, two commonly used models of provoked convulsions. RESULTS: In the Irwin test, theophylline induced convulsions in 1 out of 6 rats at 128 mg/kg. Paroxysmal/seizure activity was also observed by video-EEG recording in 4 out of the 12 animals tested at 128 mg/kg, in presence of clonic convulsions in 3 out of the 4 rats. Paroxysmal activity was observed in two rats in the absence of clear behavioral symptoms, indicating that some precursor signs can be detected using video-EEG. Clear pro-convulsant activity was shown over the dose-range 32-128 mg/kg in the ECS threshold and PTZ-induced convulsions tests. DISCUSSION: Evaluation of spontaneous convulsions provides information on the therapeutic window of a drug and the translational value of the approach is increased by the use of video-EEG. Tests based on provoked convulsions further complement the evaluation since they try to mimic high risk situations. Measurement of both spontaneous and provoked convulsions improves the evaluation of the pro-convulsant risk of novel pharmacological substances.