Pharmacological and Behavioral Characteristics of Interactions between Vigabatrin and Conventional Antiepileptic Drugs in Pentylenetetrazole-Induced Seizures in Mice: An Isobolographic Analysis

Abstract

To characterize the anticonvulsant effects and types of interactions exerted by mixtures of vigabatrin (VGB) and conventional antiepileptic drugs (valproate (VPA), ethosuximide (ESM), phenobarbital (PB), and clonazepam (CZP)) in pentylenetetrazole (PTZ)-induced seizures in mice, the isobolographic analysis for three fixed-ratio combinations of 1 : 3, 1 : 1, and 3 : 1 was used. The adverse-effect profile of the combinations tested, at the doses corresponding to their median effective doses (ED 50 ) at the fixed-ratio of 1 : 1 against PTZ-induced seizures, was determined by the chimney (motor performance), step-through passive avoidance (long-term memory), pain threshold (pain sensitivity), and Y-maze (general explorative locomotor activity) tests in mice. Additionally, the observed isobolographic interactions were verified in terms of a pharmacokinetic interaction existence. VGB combined with PB or ESM exerted supra-additive (synergistic) interactions against the clonic phase of PTZ-induced seizures, which was associated with the increment of PB or ESM concentrations in the brains of examined animals. The remaining combinations tested (ie VGB þ VPA and VGB þ CZP) occurred additive in the PTZ test, which was associated with no significant changes in the brain concentrations of VPA and CZP. None of the examined combinations exerted motor impairment in the chimney test in mice. In the standard variant of passive avoidance task (current of 0.6 mA; 2 s of stimulus duration), the combinations of VGB þ CZP and VGB þ VPA significantly affected long-term memory in mice. Moreover, VGB in a dose-dependent manner lengthened the latency to the first pain reaction in the pain threshold test in mice. The modified variant of step-through passive avoidance task (current of 0.6 mA; stimulus duration based on the latency from the pain threshold test) revealed no significant changes in the long-term memory of animals for the combinations of VGB þ VPA and VGB þ CZP; so the observed effects in the standard variant of passive avoidance task were a result of the antinociceptive effects produced by VGB. In the Y-maze test, VGB also, in a dose-dependent manner, increased the general explorative locomotor activity of the animals tested. Similarly, the total number of arm entries in the Y-maze was significantly increased for the combinations of VGB þ CZP and VGB þ ESM, but not for VGB þ PB and VGB þ VPA. The application of VGB in combination with PB, ESM, CZP, and VPA suppressed the clonic phase of PTZ-induced seizures, having no harmful or deleterious effects on behavioral functioning of the animals tested, which might be advantageous in further clinical practice.

Effects of Yokukansan, a Traditional Japanese Medicine, on Memory Disturbance and Behavioral and Psychological Symptoms of Dementia in Thiamine-Deficient Rats

“…19) In the present study, the acquisition trials were performed in rats still receiving the normal diet before drug-treatment. Although we did not examine about the individual's pain threshold, all animals in each group learned to stay in the illuminated compartment to avoid electric shock by the fifth day of the learning process.…”

Anti-convulsant Effect and Mechanism of Astragalus mongholicus Extract In Vitro and In Vivo: Protection Against Oxidative Damage and Mitochondrial Dysfunction

“…The general clonus was characterized by forelimb clonus followed by full clonus of the body. The time of the onset of clonic convulsions, the duration of clonic convulsions, and the percentage of seizure were all recorded [26].…”

Isobolographic additivity among lacosamide, lamotrigine and phenobarbital in a mouse tonic-clonic seizure model

“…Generally, drugs or their mixtures that significantly affect motor performance in animals disturb coordination or make the animals unable to climb backward up the plastic Plexiglas tube within 60 s. 36,37 Similarly, in the passive avoidance test, drugs or their mixtures that significantly affect the animals' long-term memory may impair memory acquisition and/or remembering in experimental animals, which manifests by the entrance of the mice into the dark box of the passive avoidance apparatus without a period of staying in the light compartment for up to 180 s. 38,39 In the grip-strength test, drugs or their mixtures that significantly alleviate skeletal muscular strength induce flaccidity of the animal's bodies or reduce muscle tension in the mice that manifest in a low force in grasping and pulling the squared stainless steel wire mesh connected to the electronic dynamometer. 40,41 Of note, the mixture of LCM, LTG and PB was administered to animals in doses corresponding to the ED 50 exp value obtained in the MES-induced seizure test.…”