EFFECT OF ALPRAZOLAM AND KETAMINE ON SEIZURES INDUCED BY TWO DIFFERENT CONVULSANTS

Summary: Effect of two anticonvulsants with different mechanism of action, i.e. alprazolam and ketamine, was tested in two types of seizure activity. The first one was induced by N-(3,5-dimethoxy-4-propoxyphenylethyl)-aziridine, the second one by pentylenetetrazol. While alprazolam alleviated both the minimal as well as major paroxysms, ketamine supressed only major seizures. These effects are discussed in terms of the both N-methyl-D-aspartate and GABA receptors involvement.


Material and Methods
The experiments were carried out on a total number of 144 male Wistar rats (VELAZ, Praha), weighing 200 -260 g.
The animals were fed with standard Larsen diet and had free access to water. The rats were randomly divided into groups of 8 animals. Occurence of abnormal signs, especially the feature and intensity of the convulsions, was evaluated according to specially elaborated scale (10,11), described in details previously (5). Maximum rate in this scale (equal to 5) corresponds to the generalized tonic-clonic seizures (convulsions) represented by the loss of the righting reflex at the beginning of the tonic phase and tonicclonic seizures involving muscles of forelimbs, hindlimbs, and whole body.
FAZ-4 was administered intraperitoneally in a dose of 50 mg/kg. Its effect was compared with the model convulsive drug PTZ, injected subcutaneously in a dose of 100 mg/kg. Both convulsants were freshly dissolved in saline. Alprazolam (VÚFB, Prague) and ketamine (KetalarR, Parke-Davis, Madrid) were given intraperitoneally either 30 minutes prior, or 1 minute subsequently, to administration of the convulsants tested. Doses used were 0,1 and 0,5 mg/kg for alprazolam, 10 and 25 mg/kg for ketamine. Following the administration of the drugs, the animals were placed into the experimental cage and individually observed for a period of 30 minutes after the last injection. The animals were always assigned the highest convulsive score observed and the average score was calculated for all groups (always 8 animals in each) and doses. The lethality of the animals within 48 hours after all experiments was recorded. The results were statistically evaluated by means of t-test. The level of significance was set at the 5% level.

Results
A lack of any tonic component of major paroxysm following DSP-4 was confirmed with respect to PTZ (compa- 9 ORIGINAL ARTICLE

Josef Herink
Military Medical Academy J. E. Purkyně, Hradec Králové; (Rector: doc. MUDr. S. Býma, CSc.) Summary: Effect of two anticonvulsants with different mechanism of action, i.e. alprazolam and ketamine, was tested in two types of seizure activity. The first one was induced by N-(3,5-dimethoxy-4-propoxyphenylethyl)-aziridine, the second one by pentylenetetrazol. While alprazolam alleviated both the minimal as well as major paroxysms, ketamine supressed only major seizures. These effects are discussed in terms of the both N-methyl-D-aspartate and GABA receptors involvement.
re upper and bottom left columns in Figures). Doses of both convulsants tested represent more than LD50 value. Alprazolam exerted a biphasic effect on the PTZ convulsions. The lower dose used increased intensity of these symptoms, while for the higher dose a strong anticonvulsive effect, especially in case of subsequent administration, was observed (Fig. 1, above). On the contrary, alprazolam always showed anticonvulsive effect against FAZ-4 induced seizures, with exception of prior administration of the lower dose used (Fig. 1, below). In addition to it, alprazolam had a strong positive effect on survival of animals following administration of all doses of convulsants tested. Ketamine suppressed the PTZ convulsions at the higher dose tested (Fig. 2, above), subsequent administration of this drug (i.e., 1 minute after PTZ) was more effective than that of prior injection (i.e., 30 minutes before PTZ). Ketamine was more effective in the suppression of the FAZ-4 induced convulsion in case of subsequent administration of both doses tested (Fig. 2, below). Ketamine decreased significantly the lethality in animals. This protection was more evident in PTZ than in DSP-4 intoxication.

Discussion
Convulsive effects and their influence is connected directly or indirectly with number of neuromediators, similarity as it was demonstrated for cholinergic and peptidergic systems (1,4) or organophosphates (2). PTZ is the prototype agent in the class of systemic convulsants. Nevertheless its mechanism of action is only poorly understood. At a synaptic level PTZ appears to interact with the GABA receptorbenzodiazepine complex (4,12). However other mechanisms for PTZ-induced seizures must also be important, we suppose that it would be NMDA-receptors involvement with respect especially to the major paroxysms. Anticonvulsant tested suppressed seizures in different manner. Alprazolam was effective against minimal as well as major seizures, while ketamine suppressed only major seizures. Regarding to presumed N-methyl-D-aspartate (NMDA) antagonistic properties of ketamine, there is a little possibility of the involvement of these receptor system in the origin and propagation of minimal seizure phenomenon (14,15). Strong anticonvulsive activity of benzodiazepines, especially alprazolam, suggests the GABA receptorchloride ionophore complex involvement in the origin and propagation not only in case of PTZ-but FAZ-4 convulsions too (6,7). Discrepancy between "proconvulsive" effect of lower dose tested of alprazolam on the one hand, and decreased lethality of animals in the same situation on the second hand, excludes largely straightforward chain of events leading from major paroxysm to the death itself.