Neuroprotective and neurotoxic properties of the ‘inert’ gas, xenon

D. Ma; S. Wilhelm; M. Maze; N. P. Franks

doi:10.1093/bja/89.5.739

Neuroprotective and neurotoxic properties of the ‘inert’ gas, xenon

¹Magill Department of Anaesthesia, Chelsea and Westminster Hospital and ²Biophysics Group, The Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, UK

*Correspondingauthor:Department of Anaesthetics and Intensive Care, Faculty of Medicine, Imperial College, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
^†Declaration of interest. Professor Maze and Professor Franks are Board members of an Imperial College spin‐out company (Potexeon Ltd) that is interested in developing clinical applications for medical gases, including xenon. Both Professor Franks and Professor Maze are paid consultants in this activity. In addition, Air Products have funded, and continue to fund, work in the authors’ laboratories that bears on the actions of xenon as an anaesthetic and neuroprotectant and Air Products has a financial stake in Protexeon Ltd. However, none of the work described in this manuscript was funded by either company.

Abstract

Background. Antagonists of the N‐methyl‐d‐aspartate (NMDA) subtype of glutamate receptors have been shown not only to have neuroprotective effects but also to exhibit neurotoxic properties. In this study, we used c‐Fos, a protein product of an immediate early gene, as a marker of neuronal injury to compare the neuroprotective effects of xenon and the neurotoxic properties of xenon, nitrous oxide, and ketamine, three anaesthetics with NMDA receptor antagonist properties.

Methods. We used an in vivo rat model of brain injury in which N‐methyl‐dl‐aspartic acid (NMA) is injected subcutaneously (s.c.) and c‐Fos expression in the arcuate nucleus is used as a measure of injury. To examine the neurotoxic potential of each of the three anaesthetics with NMDA receptor antagonist properties, c‐Fos expression in the posterior cingulate and retrosplenial (PC/RS) cortices was measured.

Results. Xenon dose‐dependently suppressed NMA‐induced c‐Fos expression in the arcuate nucleus with an IC₅₀ of 47 (2)% atm. At the highest concentration tested (75% atm) NMA‐induced neuronal injury was decreased by as much as that observed with the prototypical NMDA antagonist MK801 (0.5 mg kg^–1 s.c.). Both nitrous oxide and ketamine dose‐dependently increased c‐Fos expression in PC/RS cortices; in contrast, xenon produced no significant effect. If the dopamine receptor antagonist haloperidol was given before either nitrous oxide or ketamine, their neurotoxic effects were eliminated.

Conclusions. Uniquely amongst anaesthetics with known NMDA receptor antagonist action, xenon exhibits neuroprotective properties without co‐existing neurotoxicity. The reason why ketamine and nitrous oxide, but not xenon, produce neurotoxicity may involve their actions on dopaminergic pathways.

Br J Anaesth 2002; 89: 739–46