Abstract
Purpose: y‐aminobutyric acid (GABA) is the prominent inhibitory synaptic transmitter i n the central nervous system. Thc GABA‐ transport inhibitor, tiagabine, is known to cnhancc inhibitory synaptic transmission by increasing the dwelling time of GABA in the synaptic cleft and hence prolonging the inhibitory postsynaptic potentials/currents. Therefore, tiagabinc is used as an antiepileptic drug. Nowever, during repetition of epileptic discharges, a depletion of GARA in presynaptic areas should be taken into account when determining the antiepileptic effects of tiagahine. Therefore, a combination of thc GABA‐transaminase inhibitor, vigabatrin, and tiagabinc is expected to exhibit a potentiated effect on epileptiform discharges. To study the antiepileptic effccts of tiagabine and vigabatrin, we have analyzed cpileptiform discharges in in vitro epilepsy models using hippocampal slices obtained from epileptic El mice and control ddY mice. Methods: Extracellular recordings were performed in the CA3 pyramidal cell layer in slices prepared from adult (IS‐20 week‐old) male El and tldY micc. Epileptiform discharges were induced by (I) increasing K+ concentration from 3.25 to 8 mM (high‐ K+), and (2) reducing Mg2+ froin 2 to 0 mM (Mg2+‐free) of the bath solution. Tiagabine (20 pM) and vigabatrin (20 pM in the high‐ K+ model, 100 pM in the Mg2+‐free model) were applied to the bath solution. The dependent variable in this study was the rate (Hz) of epilcptiform discharges. Results: In the high‐ K+ and the Mg2+‐free solution, the occurring rate of epileptiform discharges was higher in slices of El mice through 3.5 hours of the recording period. Three hours after induction of epileptiform discharges by the high‐ K+ or Mg2+‐Mg‐free solution, the occurring rate was higher by 56% (0.25 & 0.01 Hz, n = 5, p<O.OOS) and64% (0.46 2 0.06 Hz, n =6, p<O.OI), respectively, i n slices of El mice compared to thosc in ddY mice. The sole application of tiagabinc to slices prepared from El micc did not change the occurring rate after a 3‐hour induction of epileptiform discharges in thc 2 models. In slices of ddY mice, the occurring ratc of high‐ K+. induced epileptiform discharges was suppressed to 63 k 8 % (n = 5, p<0.0004), whcrcas there was no signilicant change in the Mg2+‐free induced discharges. Thus, thc sole application of tiagabine after 3 hours o f induction of cpileptiform discharges did not show any potential supprcssioon i n the CA3 pyramidal cell layer cxcept for the high‐ K+ solution applied to slices ot ddY mice. The sole application of vigabatrin for 2.5 hours suppressed the occurring rates of high‐ K+ and Mg2+‐free‐induced epilcptiform discharges to 68 k 9 % (n = 4) and to 52 f 7 % (n = 4), respectivcly, i n El micc and to 38 k I I % (n=5) and 79 k 8 % (n=4), respectively, in ddY mice. An additional application of tiagabine to the vigabatrin application suppressed the occurring rate of epilcptiform discharges to 4 2 2 o/o and to 15 f 6 % in slices from El mice in the high‐ K+ and thc Mgfree solution, respectively, while in ddY micc it cornpletely blocked them in thc high‐ K+ solution and inhibited them lo 4 f 2 % i n the Mg2+ free solution. Conclusion: A combined application 01 GABA‐transport inhibitor tiagabine with GARA‐transaminase inhihitor vigahatrin revealed potcntiatcd anticpileptic effects. Depletion of prcsynaptic GABA during long‐lasting repetitive epileptiform discharges may be restored by vigabairin, and the rclcescd GABA concenti‐ation may he preserved in thc synaptic area by tiagabine.
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