To the Editor:--Bansinath et al. reported the effects of propofol on seizures induced in mice by a variety of chemical agents. Chemoconvulsants, which putatively act on GABAA, glycine, or glutamate receptor subtypes, were examined. The authors correctly emphasize the importance of using both in vivo and in vitro paradigms to understand the mechanism of anesthesia. However, they suggest that there is a disparity between their results and the information available from in vitro studies regarding the effects of propofol on excitatory amino acid receptors.
It is evident from Bansinath et al.'s Table 3 that propofol reduced the incidence of NMDA-induced convulsions, and this anticonvulsant effect was observed at all concentrations of NMDA tested. Moreover, the slopes of the lines in the log-probit plot (their Figure 2(C)) were similar, suggesting that the anticonvulsant property of propofol was mediated in part through modulation of the NMDA receptor. The calculated effective dose of NMDA that induced seizures in 50% of mice was apparently similar in the presence or absence of propofol. These data are consistent with in vitro studies that indicate propofol causes a noncompetitive inhibition of the NMDA receptor. [2,3]Propofol is thought to modulate the NMDA receptor at a domain other than the agonist recognition site and, hence, would not influence the affinity of receptor for agonist. Accordingly, in vitro studies predict that propofol would reduce the incidence of NMDA-induced seizure activity without affecting the calculated EC50.
Bansinath et al. also observed that propofol increased the incidence of kainate- and quisqualate-induced seizures. Propofol failed to produce a consistent effect on kainate-evoked responses recorded from cultured mouse hippocampal neurons, possibly because of the variety of kainate receptor subunits present in native neurons. However, examination of specific subtypes of non-NMDA receptors expressed in Xenopus oocytes demonstrated that propofol enhanced the currents recorded from the alpha1(GluR1) subfamily of AMPA/quisqualate-sensitive channels. The effects of propofol on non-NMDA receptors are highly dependent on the subunit examined. Furthermore, kainate activates the AMPA/quisqualate receptors, whereas quisqualate activates the metabotropic receptor, a G-protein coupled glutamate receptor. These chemoconvulsants are not sufficiently selective to make inferences regarding their behavioral properties and specific receptor populations.
Because of the enormous complexity of neuronal circuitry, it is generally difficult to link the clinical effects of anesthetics to specific receptors. However, the data presented by Bansinath et al. are consistent with propofol's demonstrated ability to inhibit the NMDA receptor and enhance certain subtypes of non-NMDA glutamate receptors.
Beverley A. Orser, MD, Ph.D., Assistant Professor of Anaesthesia, University of Toronto, Department of Anaesthesia, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5
John F. MacDonald, Ph.D., Professor of Physiology, University of Toronto, 1 Kings College Circle, Toronto, Ontario, Canada M5S 1A8