title: Pre- rather than co-application of vigabatrin increases the efficacy of tiagabine in hippocampal slices.
abstract: 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.
authors.affiliation: Institute of Physiology, University of Münster, Münster, Germany. kohling@uni-muenster.de
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Köhling
authors.forename: Klaus
authors.initials: K
authors.lastname: König
authors.forename: Anne
authors.initials: A
authors.lastname: Lücke
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayer
authors.forename: Peter
authors.initials: P
authors.lastname: Wolf
authors.forename: Erwin-Joseph
authors.initials: EJ
authors.lastname: Speckmann
mesh_terms: 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
chemical_list: D000927:Anticonvulsants; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin; D008274:Magnesium; D000078308:Tiagabine