Effects of the Anticonvulsant Losigamone and Its Isomers on the GABAA Receptor System
Version of Record online: 3 AUG 2005
Volume 36, Issue 10, pages 983–989, October 1995
How to Cite
Dimpfel, W., Chatterjee, S. S., Nöldner, M. and Ticku, M. K. (1995), Effects of the Anticonvulsant Losigamone and Its Isomers on the GABAA Receptor System. Epilepsia, 36: 983–989. doi: 10.1111/j.1528-1157.1995.tb00956.x
- Issue online: 3 AUG 2005
- Version of Record online: 3 AUG 2005
- Received June 21, 1994; revision accepted April 13, 1995.
Summary: We conducted in vitro studies to clarify the possible involvement of GABA, 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, ≤100 μM losigamone did not affect the specific binding of [3H]GABA, [3H]flunitrazepam, or [35S]t-butyl-bicyclo-phosphorothionate (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 M on 336Cl 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.