topiramate and loreclezole

The broad spectrum anticonvulsant topiramate modulates multiple voltage-gated and ligand-gated channels, including γ-aminobutyric acid type A (GABA(A)) receptors. Previously, we found a strong β-subunit influence on the effects of topiramate on heteromeric GABA(A) receptors. Here, we tested the hypothesis that homomeric GABA(A) receptors comprised of either β(1)- or β(3)-subunits will contain a functional binding site for topiramate. For comparison, we also examined the effects of pentobarbital and loreclezole which exhibit β-subunit dependence as well. We expressed β(1)- and β(3)-homomeric receptors in Xenopus laevis oocytes and acquired electrophysiological responses using two-electrode voltage clamp techniques. Oocytes expressing β-homomers were insensitive to GABA and had hyperpolarized resting membrane potentials, decreased input resistances, increased holding currents and picrotoxin-induced outward currents consistent with the expression of non-ligand-mediated, spontaneous channel openings of β-homomers. Similar to picrotoxin, application of topiramate, pentobarbital and loreclezole inhibited β(1)-homomers. In contrast, these compounds activated β(3)-homomers. As with heteromeric receptors, topiramate and pentobarbital modulation of β(1)- and β(3)-homomers exhibited rebound currents indicating an open channel block or stabilization of desensitization. Interaction studies suggested competition between topiramate, loreclezole and pentobarbital for activation of β(3)-homomers, whereas topiramate inhibitory actions were non-competitive with pentobarbital but competitive with loreclezole. In summary, β(1)- and β(3)-subunits have binding site(s) for topiramate that elicit functional effects with similarities to heteromeric receptor responses. From this foundation, contributions of residues and other subunits in binary and ternary heteromeric receptors can be explored to gain a complete understanding of topiramate actions on complex heteromeric GABA(A) receptors.

Topics: Animals; Drug Interactions; Electrophysiological Phenomena; Fructose; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Inhibitory Concentration 50; Membrane Potentials; Oocytes; Pentobarbital; Picrotoxin; Rats; Receptors, GABA-A; Topiramate; Transfection; Triazoles; Xenopus laevis

The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis.. Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established.. With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task.. LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.

Topics: Animals; Anticonvulsants; Behavior, Animal; Carbamazepine; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Electroshock; Felbamate; Fructose; Kindling, Neurologic; Lamotrigine; Male; Mice; Motor Activity; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Seizures; Topiramate; Triazines; Triazoles