Pre- rather than co-application of vigabatrin increases the efficacy of tiagabine in hippocampal slices.
OBJECTIVE
The antiepileptic drug vigabatrin (VGB) increases intracellular availability of the inhibitory transmitter gamma-aminobutyric acid (GABA) by inhibition of GABA-transaminase. A blockade of the GABA uptake is the main mechanism of action of tiagabine (TGB). Based on this, the two antiepileptic drugs (AEDs) can be speculated to act synergistically so that their combined antiepileptic efficacy is supraadditive.


METHODS
To test this, experiments were performed on hippocampal slices of guinea-pigs. As an epilepsy model, epileptiform field potentials (EFPs) were induced by omission of Mg2+ from the bath solution and recorded in stratum pyramidale of the CA3 region. VGB (7.5 microM) and TGB (0.75 microM) were added to the superfusate.


RESULTS
VGB, given alone, failed to decrease the repetition rate of EFPs. Similarly, TGB applied alone only transiently led to a nonsignificant reduction of the EFP frequency. Combining VGB and TGB, their suppressive efficacy increased, yielding a significant reduction of EFP frequency, which, however, again did not persist. Pretreatment of the preparations with VGB for 2 h, followed by additional application of TGB, or TGB alone, drastically and persistently potentiated the effects.


CONCLUSIONS
These results demonstrate that VGB and TGB show favorable pharmacodynamic interactions, provided VGB is allowed to block intracellular GABA degradation before GABA uptake block by TGB.
Köhling
Rüdiger
R
Institute of Physiology, University of Münster, Münster, Germany. kohling@uni-muenster.de
König
Klaus
K
Lücke
Anne
A
Mayer
Thomas
T
Wolf
Peter
P
Speckmann
Erwin-Joseph
EJ
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D046508:Culture Techniques; D004357:Drug Synergism; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D008274:Magnesium / Q000502:physiology; D009557:Nipecotic Acids / Q000494:pharmacology*; D011292:Premedication; D000078308:Tiagabine; D020888:Vigabatrin / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin; D008274:Magnesium; D000078308:Tiagabine