PROPOFOL MODULATES THE EFFECTS OF CHEMOCONVULSANTS ACTING AT GABAERGIC, GLYCINERGIC, AND GLUTAMATE-RECEPTOR SUBTYPES

Background: Propofol has been used to treat status epilepticus, but it s use in patients with seizure disorders remains controversial, becaus e of concerns that it produces paroxysmal motor phenomenon. Chemoconvu lsants act by known discrete mechanisms and neurotransmitters, and the refore, they are useful tools for screening anticonvulsant activity. T he main objective of this study was to characterize the effect of prop ofol pretreatment on convulsions induced by picrotoxin, bicuculline, a nd strychnine, all which decrease inhibitory neurotransmission, and by N-methyl-D-aspartic acid, kainic acid, and quisqualic acid, which enh ance excitatory neurotransmission. Methods: Groups of male Swiss Webst er mice (n greater than or equal to 10/group) were given either vehicl e (intralipid, 10 ml . kg(-1), control groups) or propofol (50 mg . kg (-1), test groups) injected intraperitoneally. Five min after injectio n, 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), qu isqualic acid (1-10 nmol), kainic acid (0.252-2 mole), or strychnine ( 1.35-10.78 nmol) injected intracerebroventricularly. The number of ani mals with convulsions after each dose was recorded. Analysis of statis tical significance was based on the log-probit lines of the quantal do se-response for the respective control and test groups, calculated 50% effective doses (ED50), the potency ratios (ED50(higher)/ED50(lower)) and their 95% confidence limits. Results: Propofol pretreatment decre ased the potency ratio of both bicuculline (0.47, 95% confidence inter val = 0.23-0.94) and picrotoxin (0.61, 0.47-0.79), signifying an antic onvulsant effect, Conversely, propofol pretreatment significantly enha nced the convulsive potency of kainic acid (potency ratio and 95% conf idence interval = 1.66, 1.21-2.29), quisqualic acid (3.1.7, 1.98-5.09) , and strychnine (1.76, 079-3.89). Conclusions: Current results sugges t that propofol augments the paroxysmal motor phenomenon induced by ka inic acid, quisqualic acid, and strychnine. This action may be, at lea st partly, responsible for the motor manifestations reported after pro pofol administration. These in vivo results on modulation of gamma-ami nobutyric acid, glycine, lpha-amino-3-hydroxy-5-methyl-4-isoxazoleprop ionic acid, and kainate receptor-mediated transmission may be of signi ficance in understanding the mechanism of propofol action at the excit atory and inhibitory amino acid receptors.