Beneficial interaction between vigabatrin and valproate against seizures induced by pentylenetetrazole in mice.
The anticonvulsant effects of adding a non-protective dose of vigabatrin (VGB) to increasing single doses of sodium valproate (VPA) against seizures induced by 110 mgkg(-1) of pentylenetetrazole (PTZ) or by 4.5 mgkg(-1) of picrotoxin (PIC) were compared in CD1 mice with those of VPA alone and vice versa. Neurotoxicity was evaluated by the rotarod test. The study also assessed changes in concentrations of anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate in the whole brain. VGB increased the potency ratio of VPA against PTZ (1.62, P < 0.05) but not against PIC (1.08, n.s.). VGB slightly decreased the neurotoxicity of VPA (0.93, n.s.) and the protective index of VPA was, therefore, increased from 1.93 to 3.34 for the PTZ model and from 1.40 to 1.61 for the PIC model. VGB did not modify brain concentrations of VPA, and increased brain GABA in relation to VPA alone. On the other hand, VGB did not achieve a complete protection neither against seizures induced by PTZ nor against seizures induced by PIC and a non-protective dose of VPA did not significantly modify the effects of increasing doses of VGB. In conclusion, the addition of a non-protective dose of VGB increased the anticonvulsants effects and the protective index of VPA in the PTZ model. A more than expected brain GABA increase together with the lack of a pharmacokinetic interaction support a pharmacodynamic basis for this interaction.
Cuadrado
Antonio
A
Clinical Pharmacology Service, Marqués de Valdecilla University Hospital, Department of Physiology and Pharmacology, University of Cantabria School of Medicine, Avda. de Valdecilla, s/n, E-39008 Santander, Spain.
Armijo
Juan A
JA
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003292:Convulsants; D004357:Drug Synergism; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole; D014635:Valproic Acid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D020888:Vigabatrin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D003292:Convulsants; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D020888:Vigabatrin; D010433:Pentylenetetrazole