Gabapentin potentiation of the antiepileptic efficacy of vigabatrin in an in vitro model of epilepsy.
1. An enhancement of promoted release of gamma-aminobutyric acid (GABA) and a change in GABA-metabolism have been suggested as mechanisms of action of gabapentin. Vigabatrin is supposed to act mainly via inhibition of GABA-transaminase but it also interferes with GABA-release and GABA-uptake. On the basis of these mechanisms of action, a pharmacodynamic interaction of the two antiepileptic drugs could be supposed which might be of relevance in the sense of a rational polypharmacy. 2. To address the aforementioned hypothesis, experiments were carried out on hippocampal slices (n=107) of guinea-pigs (n=70). Epileptiform field potentials (e.f.p.) were induced by omission of magnesium from the bath solution and recorded in the stratum pyramidale of the CA3 region. Gabapentin (30-600 microM; 5.1-102.72 microg ml(-1)), vigabatrin (50-200 microM, 6.45-25.8 microg ml(-1)) and the GABA(A)-receptor antagonist bicuculline (100 microM) were added to the bath solution for 3 h. 3. Gabapentin, in concentrations up to 600 microM, failed to decrease the repetition rate or duration of e.f.p. (n=19). However, vigabatrin, evoked a dose-dependent reduction of the repetition rate of e.f.p. For a concentration of 100 microM (12.9 microg ml(-1)) there was a reduction down to 48+/-5% (mean+/-s.e.mean) of the initial value within 3 h (n=11). With simultaneous administration of vigabatrin (100 microM) and gabapentin (60 microM) for 3 h (n=15), the repetition rate of e.f.p. decreased down to 8+/-3%, which is significantly different from the values obtained after administration of 100 microM vigabatrin alone (P<0.0001). Both, the antiepileptic effect of vigabatrin alone and the enhancement by gabapentin were blocked by the GABA(A)-receptor antagonist bicuculline (100 microM, n=16). 4. These results demonstrate that gabapentin is able to augment the antiepileptic effects of vigabatrin significantly. It is possible that a change in the GABA-release machinery is induced by vigabatrin which then can be augmented by gabapentin.
Lücke
A
A
Institute of Physiology, University of Münster, Germany.
Musshoff
U
U
Köhling
R
R
Osterfeld
M
M
Mayer
T
T
Wolf
P
P
Schütte
W
W
Speckmann
E J
EJ
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004827:Epilepsy / Q000188:drug therapy; D018756:GABA Antagonists / Q000494:pharmacology*; D000077206:Gabapentin; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008275:Magnesium Deficiency; D019338:Polypharmacy; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D018756:GABA Antagonists; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D001640:Bicuculline