Antiepileptic action induced by a combination of vigabatrin and tiagabine.
Vigabatrin, an inhibitor of GABA breakdown by GABA transaminase and of GABA transporter isoform 1 (GAT1), and tiagabine, a highly specific inhibitor of GAT1, have successfully been applied in the treatment of epilepsy. We investigated the effects of individual and combined application of these drugs on GAT1 expressed in Xenopus oocytes, and examined the effects on epileptiform discharges in the CA3 area of brain slices of genetically epileptic El and control ddY mice, and on the occurrence of seizures in El mice. Simultaneous application of vigabatrin and tiagabine inhibited epileptiform discharges induced by high-K+ solution in the brain slices in an antagonistic fashion. The degree of inhibition by tiagabine after pre-treatment with vigabatrin was additive in ddY mice and synergistic in El mice. In Mg2+-free solution, co-treatment by the two drugs produced additive inhibition in slices from both mouse strains, but pre-treatment with vigabatrin produced synergistic inhibition in slices only from ddY mice. In the slices from El mice, a combination of drugs resulted in additive effects in both co- and pre-treatment by the drugs. Although these drugs are also effective in vivo at suppressing seizure occurrence in El mice, the combined application does not show synergistic effects, but rather is antagonistic under the experimental conditions in this particular variant of epilepsy. The synergistic inhibition of epileptiform discharges in brain slices may, in part, have originated from the complex interaction with GAT1. In experiments on the GAT1 expressed in oocytes it could be demonstrated that synergistic inhibition occurs only at low concentration (0.1 nM) of vigabatrin. This illustrates that the oocytes may form a powerful test system for drug screening and investigation of complex drug interactions. These results present a novel interpretation of synergistic inhibition of certain epileptic discharges using vigabatrin and another drug, and that for successful synergistic treatment of epilepsies carefully designed timed dosage regimens are essential.
Fueta
Y
Y
Department of Med. Tech., School of Health Sciences, Univ. Occupat./Environmental Health, Iseigaoka 1-1, Yahatanishi-ku, Kitakyushu 807-8555, Japan. yukiko@med.uoeh-u.ac.jp
Kunugita
N
N
Schwarz
W
W
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004558:Electric Stimulation / Q000009:adverse effects; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D009557:Nipecotic Acids / Q000627:therapeutic use*; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D011189:Potassium Chloride / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D000078308:Tiagabine; D013997:Time Factors; D020888:Vigabatrin / Q000627:therapeutic use*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D004338:Drug Combinations; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D020888:Vigabatrin; D008274:Magnesium; D000078308:Tiagabine