tetronic-acid and Epilepsy

We conducted in vitro studies to clarify the possible involvement of GABAA receptor-mediated processes in the anticonvulsant effects of losigamone and its optical isomers AO-242 (+ losigamone) and AO-294 (- losigamone). In binding experiments with cortical and cerebellar membrane preparations of rat brain, < or = 100 microM losigamone did not affect the specific binding of [3H]GABA, [3H]flunitrazepam, or [35S]t-butyl-bicyclophosphorothionate (TBPS) to their receptors. Losigamone, however, in concentrations of 10(-8)-10(-5) M, stimulated 36Cl influx into spinal cord neurons in the absence of exogenous GABA. This effect was inhibited by the GABA antagonists bicuculline (BIC) and picrotoxin (PIC). Losigamone 10(-5) M potentiated the effect of a suboptimal concentration of exogenous GABA 10(-5) M on 36 Cl influx. Both isomers of losigamone likewise stimulated 36Cl influx into spinal cord neurons, and these effects were similarly antagonized by BIC and PIC. Losigamone and its optical isomers AO-294 and AO-242 antagonized potassium-induced hyperexcitability in rat hippocampal slices concentration dependently. There were no clear differences in the potencies of losigamone, AO-242, or AO-294. However, AO-294 and AO-242 differed significantly in their ability to suppress TBPS-induced hyperexcitability of hippocampal slices. Such observations demonstrate that although losigamone does not bind to GABA, benzodiazepine (BZD) or PIC binding sites of the neuronal chloride channel, it is capable of stimulating 36Cl influx in the spinal cord neurons by a GABA-sensitive mechanism and at a side distant from the GABA channel.

Topics: Animals; Anticonvulsants; Bridged Bicyclo Compounds, Heterocyclic; Cerebellum; Cerebral Cortex; Chloride Channels; Chlorine; Convulsants; Dose-Response Relationship, Drug; Epilepsy; Female; Furans; gamma-Aminobutyric Acid; Hippocampus; In Vitro Techniques; Isomerism; Male; Mice; Mice, Inbred C57BL; Radioisotopes; Rats; Rats, Sprague-Dawley; Receptors, GABA-A

We have investigated the effects of a new class of anticonvulsants, the tetronic acid derivatives AO33 (generic name: losigame) and AO78, on field potentials, extracellular calcium concentration changes and intracellular potentials in rat hippocampal slices treated with the non-competitive GABAA antagonist picrotoxin (PTX). The tetronic acid derivatives reduced and eventually blocked spontaneous epileptiform events, induced by 10 to 30 microM PTX. Stimulus induced burst discharges were shortened in duration, but not blocked. Extracellular calcium concentration changes and associated slow negative field potentials were diminished in a dose dependent manner. Intracellular recordings revealed no effect of AO33 on resting membrane potential, little effect on input resistance, a small increase in the threshold of action potentials and an attenuation of stimulus induced paroxysmal depolarisation shifts (PDSs). Spontaneous PDSs initially decreased in duration until they were no longer observable.

Topics: Action Potentials; Animals; Anticonvulsants; Epilepsy; Female; Furans; Hippocampus; In Vitro Techniques; Picrotoxin; Rats; Rats, Inbred Strains