Liaisons dangereuses? General anaesthetics and long-term toxicity in the CNS

We do not know how general anaesthetics cause their desired effects. Contrary to what has been thought until relatively recently, the clinical state of anaesthesia consists of multiple components that are mediated via interaction of the anaesthetic drugs with different targets on the molecular, the cellular, the network and the structural-anatomical levels. The mechanisms by which some of these drugs induce the different components of "anaesthesia" may be rather specific: discrete mutations of single amino acids in specific proteins profoundly affect the ability of certain anaesthetics to achieve specific endpoints. Despite this potential specificity, inhalational anaesthetics are present in the body at very high concentrations during surgical anaesthesia. Due to their lipid solubility, general anaesthetics dissolve in every membrane, penetrate into organelles and interact with numerous cellular structures in multiple ways. A priori, it is therefore not unreasonable to assume that these drugs have the potential to cause insidious changes in the body other than those acute and readily apparent ones that we routinely monitor for. Some changes may wane within a short time after removal of the drug (e.g. the suppression of immune cell function). Others may persist after complete removal of the drug and even become self-propagating (e.g. spread of malignant cells, the beta-oligomerization of proteins), still others may be irreversible (e.g. the induction of apoptosis in the central nervous system) but of unclear significance. This article will focus on evidence for anaesthetic toxicity in the central nervous system, which appears to be susceptible to anaesthetic neurotoxicity primarily at the extremes of ages but via different pathways: in the neonate, during the period of most intense synaptogenesis, anaesthetics can induce excessive apoptosis; in the aging brain subtle cognitive dysfunction can persist long after clearance of the drug and processes resembling neurodegenerative disorders may be accelerated. At all ages, anaesthetics affect gene expression regulating protein synthesis in poorly understood ways. While it seems reasonable to assume that the vast majority of our patients completely restore homeostasis after general anaesthesia, exposure to these drugs probably has more profound and longer-lasting effects on the brain than heretofore imagined.