Propofol modulates the effects of chemoconvulsants acting at GABAergic, glycinergic, and glutamate receptor subtypes.

Abstract

Propofol has been used to treat status epilepticus, but its use in patients with seizure disorders remains controversial, because of concerns that it produces paroxysmal motor phenomenon. Chemoconvulsants act by known discrete mechanisms and neurotransmitters, and therefore, they are useful tools for screening anticonvulsant activity. The main objective of this study was to characterize the effect of propofol pretreatment on convulsions induced by picrotoxin, bicuculline, and strychnine, all which decrease inhibitory neurotransmission, and by N-methyl-D-aspartic acid, kainic acid, and quisqualic acid, which enhance excitatory neurotransmission. Groups of male Swiss Webster mice (n > or = 10/group) were given either vehicle (intralipid, 10 ml.kg-1, control groups) or propofol (50 mg.kg-1, test groups) injected intraperitoneally. Five min after injection, convulsions were induced with either bicuculline (1.36-5.44 nmoles), picrotoxin (0.21-1 nmol), N-methyl-D-aspartic acid (0.51-2 nmol), quisqualic acid (1-10 nmol), kainic acid (0.252-2 mole), or strychnine (1.35-10.78 nmol) injected intracerebroventricularly. The number of animals with convulsions after each dose was recorded. Analysis of statistical significance was based on the log-probit lines of the quantal dose-response for the respective control and test groups, calculated 50% effective doses (ED50), the potency ratios (ED50higher/ED50lower) and their 95% confidence limits. Propofol pretreatment decreased the potency ratio of both bicuculline (0.47, 95% confidence interval = 0.23-0.94) and picrotoxin (0.61, 0.47-0.79), signifying an anticonvulsant effect. Conversely, propofol pretreatment significantly enhanced the convulsive potency of kainic acid (potency ratio and 95% confidence interval = 1.66, 1.21-2.29), quisqualic acid (3.17, 1.98-5.09), and strychnine (1.76, 0.79-3.89). Current results suggest that propofol augments the paroxysmal motor phenomenon induced by kainic acid, quisqualic acid, and strychnine. This action may be, at least partly, responsible for the motor manifestations reported after propofol administration. These in vivo results on modulation of gamma-aminobutyric acid, glycine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptor-mediated transmission may be of significance in understanding the mechanism of propofol action at the excitatory and inhibitory amino acid receptors.