2,3-Butanedione monoxime protects mice against the convulsant effect of picrotoxin by facilitating GABA-activated currents.
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.
Brightman
T
T
Department of Pharmacology and Toxicology, New Jersey Medical School (UMDNJ), Newark 07103-2714, USA.
Ye
J H
JH
Ortiz-Jimenez
E
E
Flynn
E J
EJ
Wu
W H
WH
McArdle
J J
JJ
D000818:Animals; D000927:Anticonvulsants; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007031:Hypothalamus / Q000187:drug effects; D008297:Male; D051379:Mice; D010852:Picrotoxin / Q000494:pharmacology*; D018079:Receptors, GABA / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced*
D000927:Anticonvulsants; D002801:Cholinesterase Reactivators; D003931:Diacetyl; D010852:Picrotoxin; D018079:Receptors, GABA; C004717:diacetylmonoxime