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Enhancement of Antiepileptic Effects of the GAUA‐Transport Inhibitor Tiagabine by GABA‐Transaminase Inhibitor Vigabatrin
Author(s) -
Fueta Yukiko,
Schwarz Wolfgang,
Fukata Koich,
Ohno Koki
Publication year - 2000
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.2000.tb02233.x
Subject(s) - tiagabine , vigabatrin , gaba transaminase , inhibitory postsynaptic potential , chemistry , anticonvulsant , neurotransmission , synaptic cleft , pharmacology , gaba transporter , epilepsy , neuroscience , medicine , biochemistry , biology , enzyme , gabaergic , receptor , glutamate decarboxylase
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 Mg 2+ ‐Mg‐free solution, the occurring rate was higher by 56% (0.25 & 0.01 Hz, n = 5, p