Ketamine and Glutamate Receptors: Potential Toxicity of General Anesthetics during Rapid Brain Development

Abstract

The amino acid L-glutamate is generally recognized as the major excitatory neurotransmitter of the mammalian central nervous system (CNS) and glutamate receptors play a major role in fast excitatory synaptic transmission. Nmethyl- D-aspartate (NMDA)-type glutamate receptors are widely distributed throughout the CNS and operate ligandactivated ion channels. The activation and function of NMDA receptors are modulated by a variety of endogenous and exogenous compounds. Various anesthetic protocols have been used in pediatric medicine for many years in the absence of clear systematic assessment concerning drug exposure and possible adverse effects. It is known that most of the currently used anesthetic drugs have either NMDA receptor blocking or gamma-amino butyric acid (GABA) receptor activating properties. It has been reported that anesthetics such as ketamine, an NMDA receptor antagonist, cause neuronal cell death in rodents when administered during critical periods of development. The window of vulnerability to the neuronal effects of pediatric anesthetics seems to be restricted to the period of rapid synaptogenesis, also known as the brain growth-spurt period. Accentuated neurodegenerative mechanisms in the immature brain can thus increase neuronal susceptibility to exposure to anesthetic agents. Anesthetics that block NMDA or activate GABA receptors consistently increase cell death in the neonatal brain, suggesting that the physiological stimulation of NMDA receptors is necessary for normal neuronal synaptogenesis, differentiation, and survival during development. The main purposes of this review are to outline progress in the application of pharmacogenomic/systems approaches and animal models to systematically evaluate dose-response and time-course effects of anesthetic agents; to describe what is known about underlying mechanisms; and to define the relationship between altered NMDA receptor expression and the potential of anesthetics to cause toxicity during development. It should be mentioned that much of this discussion is based on experiments conducted only with ketamine. This is due in part to the use of ketamine in critical early studies and the volume of preclinical experimental work performed with this agent, and because comparative (rodent and nonhuman primates) data exist for this compound. The findings of the ketamine studies to date are sufficiently strong enough to cause concern for other agents which affect the same receptors.