General anesthetics and long-term neurotoxicity.

We do not know how general anesthetics cause their desired effects. Contrary to what has been thought until relatively recently, the clinical state of anesthesia consists of multiple components that are mediated via interaction of the anesthetic drugs with different targets on the molecular-cellular, the network, and the structural-anatomical levels. The molecular targets by which some of these drugs induce the different components of "anesthesia" may be rather specific: discrete mutations of single amino acids in specific proteins profoundly affect the ability of certain anesthetics to achieve specific endpoints. Despite this potential specificity, inhalational anesthetics are present in the body at very high concentrations during surgical anesthesia. Due to their lipid solubility, general anesthetics dissolve in every membrane, penetrate into every organelle, and can 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. 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., beta-oligomerization of proteins (Eckenhoff et al. 2004)], still others may be irreversible [e.g., the induction of apoptosis in the CNS (Jevtovic-Todorovic et al. 2003)] but of unclear significance. This article will focus on evidence for anesthetic toxicity in the central nervous system (CNS). The CNS appears to be susceptible to anesthetic neurotoxicity primarily at the extremes of ages, possibly via different pathways: in the neonate, during the period of most intense synaptogenesis, anesthetics can induce excessive apoptosis; in the aging CNS subtle cognitive dysfunction can persist long after clearance of the drug, and processes reminiscent of neurodegenerative disorders may be accelerated (Eckenhoff et al. 2004). At all ages, anesthetics 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 anesthesia, it is also time to acknowledge that exposure to these drugs has more profound and longer lasting effects on the brain than heretofore imagined.