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2,3-Butanedione monoxime protects mice against the convulsant effect of picrotoxin by facilitating GABA-activated
T Brightman1, J H Ye, E Ortiz-Jimenez
1Department of Pharmacology and Toxicology, New Jersey Medical School (UMDNJ), Newark 07103-2714, USA.
Abstract:
While adult mice receiving picrotoxin (PTX) alone responded with clonic and tonic-clonic seizures, this response was greatly suppressed for mice simultaneously injected with 2,3-butanedione monoxime (BDM). For example, 60% and 10% of the mice convulsed when injected (i.p.) with 3.0 mg/kg PTX alone or PTX plus 205 mg/kg of BDM, respectively. In contrast, a non-oxime analogue of BDM, 2,3-butanedione (BTD), did not have this anticonvulsant effect. In order to explore the basis for the anticonvulsant effect of BDM, we recorded GABA-activated currents (IGABA) of frontal cortical as well as ventromedial hypothalamic neurons before, during and after exposure to this oxime. BDM had a biphasic effect on IGABA. That is, high concentrations (100 microM-40 mM) decreased and lower concentrations (0.01 microM-0.001 microM) potentiated IGABA; these effects of BDM reversed upon washout of the oxime. In contrast, BTD had no effect on IGABA. Finally, when 0.001 microM BDM, 10-30 microM PTX and GABA were co-applied the inhibitory effect of the toxin on IGABA was markedly suppressed. These data suggest that the anticonvulsant effect of oximes involves facilitation of the inhibitory action of GABA.
Insights
2,3-butanedione monoxime (BDM) suppressed seizures in mice by enhancing GABA
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Picrotoxin (PTX) induces seizures in adult mice.
- 2,3-butanedione monoxime (BDM) exhibits anticonvulsant properties.
- A BDM analogue, 2,3-butanedione (BTD), lacks anticonvulsant effects.
Purpose of the Study:
- To investigate the mechanism underlying BDM's anticonvulsant activity.
- To determine BDM's effect on GABA-activated currents (IGABA).
Main Methods:
- In vivo seizure suppression tests in mice.
- Electrophysiological recordings of IGABA in cortical and hypothalamic neurons.
- Application of BDM and BTD at various concentrations.
Main Results:
- BDM significantly reduced PTX-induced seizures.
- BDM demonstrated a biphasic effect on IGABA: potentiation at low concentrations and inhibition at high concentrations.
- BTD had no effect on IGABA.
- BDM mitigated PTX's inhibitory effect on IGABA.
Conclusions:
- BDM's anticonvulsant action is mediated by its interaction with GABAergic neurotransmission.
- Oximes, like BDM, may exert anticonvulsant effects by facilitating GABA's inhibitory actions.