Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics.

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood ß-hydroxybutarate (ß-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. ß-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of ß-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

Relevance of experimental paradigms of anesthesia induced neurotoxicity in the mouse.

Routine general anesthesia is considered to be safe in healthy individuals. However, pre-clinical studies in mice, rats, and monkeys have repeatedly demonstrated that exposure to anesthetic agents during early post-natal periods can lead to acute neurotoxicity. More concerning, later-life defects in cognition, assessed by behavioral assays for learning and memory, have been reported. Although the potential for anesthetics to damage the neonatal brain is well-documented, the clinical significance of the pre-clinical models in which damage is induced remains quite unclear. Here, we systematically evaluate critical physiological parameters in post-natal day 7 neonatal mice exposed to 1.5% isoflurane for 2-4 hours, the most common anesthesia induced neurotoxicity paradigm in this animal model. We find that 2 or more hours of anesthesia exposure results in dramatic respiratory and metabolic changes that may limit interpretation of this paradigm to the clinical situation. Our data indicate that neonatal mouse models of AIN are not necessarily appropriate representations of human exposures.