Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia.

BACKGROUND: The general anesthetic gas xenon is neuroprotective and is undergoing clinical trials as a treatment for ischemic brain injury. A small number of molecular targets for xenon have been identified, the N-methyl-D-aspartate (NMDA) receptor, the two-pore-domain potassium channel TREK-1, and the adenosine triphosphate-sensitive potassium channel (KATP). However, which of these targets are relevant to acute xenon neuroprotection is not known. Xenon inhibits NMDA receptors by competing with glycine at the glycine-binding site. We test the hypothesis that inhibition of the NMDA receptor at the glycine site underlies xenon neuroprotection against hypoxia-ischemia. METHODS: We use an in vitro model of hypoxia-ischemia to investigate the mechanism of xenon neuroprotection. Organotypic hippocampal brain slices from mice are subjected to oxygen-glucose deprivation, and injury is quantified by propidium iodide fluorescence. RESULTS: We show that 50% atm xenon is neuroprotective against hypoxia-ischemia when applied immediately after injury or after a delay of 3 h after injury. To validate our method, we show that neuroprotection by gavestinel is abolished when glycine is added, confirming that NMDA receptor glycine site antagonism underlies gavestinel neuroprotection. We then show that adding glycine abolishes the neuroprotective effect of xenon, consistent with competitive inhibition at the NMDA receptor glycine site mediating xenon neuroprotection. CONCLUSIONS: We show that xenon neuroprotection against hypoxia- ischemia can be reversed by increasing the glycine concentration. This is consistent with competitive inhibition by xenon at the NMDA receptor glycine site, playing a significant role in xenon neuroprotection. This finding may have important implications for xenon's clinical use as an anesthetic and neuroprotectant.

Local GABA(A) receptor blockade reverses isoflurane's suppressive effects on thalamic neurons in vivo.

Many in vitro effects of volatile anesthetics are known, but the mechanisms of action are still under debate. Because suppression of sensory perception is one of the major goals of general anesthesia, we studied the effects of isoflurane on the processing of somatosensory information in anesthetized rats. Local iontophoretic administration of the gamma-aminobutyric acid-A (GABA(A)) receptor antagonist bicuculline in the thalamic ventral posteromedial nucleus reversed suppressive effects of isoflurane on thalamocortical relay neurons (TCNs). The action potential discharges of TCNs (n = 23) in response to defined mechanical stimulation of receptive fields seen with small concentrations of isoflurane (0.79% +/- 0.01%, mean +/- SEM) were suppressed under large concentrations (1.44% +/- 0.04%). In addition, the tonic response pattern was lost, which initially encoded the information about the stimulus features. In 70% of TCNs, bicuculline administration reestablished the initially present tonic response pattern under large isoflurane concentrations. These results indicate that isoflurane suppresses somatosensory information transfer at the thalamic level in vivo, apparently by enhancing thalamic GABA(A) receptor-mediated inhibition.

Does nitrous oxide antagonize sevoflurane-induced hypnosis?

We have studied 64 ASA I and II patients (aged 20-60 yr) to determine if nitrous oxide affects sevoflurane requirement for achieving 50% probability of no movement in response to verbal commands (MACawake). Patients were allocated randomly to one of four nitrous oxide concentration groups (0, 20, 40 and 60 vol.%). Patients in each group received sevoflurane at two different end-tidal concentrations according to a predetermined randomization table. After steady state sevoflurane and nitrous oxide concentrations had been maintained for at least 15 min, patients were assessed as being awake or asleep. The MACawake for sevoflurane was 0.63% and this was reduced significantly in a non-linear manner by increasing nitrous oxide concentration. A 50% reduction in MACawake was produced by a nitrous oxide concentration of 45%. The reduction in MACawake by nitrous oxide was non-linear; the interaction coefficient between nitrous oxide and sevoflurane being significantly less than zero (P = 0.0238), indicating that the reduction in MACawake by nitrous oxide was smaller than would be expected from simple additivity and that nitrous oxide antagonized the effects of sevoflurane in preventing response to verbal commands.