The neurotoxicity of nitrous oxide: the facts and "putative" mechanisms

Abstract

Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl-d-aspartate (NMDA)-antagonist drug, similar in nature to ketamine, another anaesthetic agent. It has been linked to post-operative cardiovascular problems in clinical studies. It is also widely known that exposure to nitrous oxide during surgery results in elevated homocysteine levels in many patients, but very little work has investigated the long term effect of these increased homocysteine levels. Now research in rodent models has found that homocysteine can be linked to neuronal death and possibly even cognitive deficits. This review aims to examine the current knowledge of mechanisms of action of nitrous oxide, and to describe some pathways by which it may have neurotoxic effects.

Figure 1

An overview of the homocysteine-mediated pathway of cell death induced by N₂O exposure. N₂O inhibits the action of vitamin B₁₂, an essential cofactor in the conversion of homocysteine to methionine. This inhibition of vitamin B₁₂ leads to a buildup of homocysteine, a toxic amino acid. Homocysteine is toxic via at least two mechanisms; increasing reactive oxygen species (ROS) leading to eventual apoptotic cell death, and NMDA receptor activation. NMDA receptor activation can lead to an increase in ROS due to an influx of calcium into the cell. While N₂O is also an NMDA antagonist, it is only effective during the course of anaesthetic exposure, while the rise in homocysteine levels induced by N₂O lasts for hours or even days, suggesting that homocysteine mediated NMDA activation would play a larger role in cell death than N₂O antagonism could counteract.