Abstract
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 β-hydroxybutarate (β-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-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.
Highlights
Volatile anesthetic agents (VAs) have been routinely used for general anesthesia for over 150 years; their development represented a major advance in human medicine [1]
Metabolic status of neonatal mice is rapidly disrupted by volatile anesthesia exposure Neonatal mice are in a ketotic state compared to adolescent or young adult (P60) animals, as has been previously reported (Fig. 1) [13,14,15,16,17]
We recently reported that exposure of post-natal day 7 (P7) neonatal mice to an anesthetizing dose of 1.5% isoflurane leads to a significant reduction in circulating levels of the ketone ß-HB by 2 hours of exposure [13], a physiologic effect of anesthesia that had not been previously reported
Summary
Volatile anesthetic agents (VAs) have been routinely used for general anesthesia for over 150 years; their development represented a major advance in human medicine [1] Despite their prevalence, the precise targets of VAs, and mechanisms underlying their pleiotropic effects, are largely undefined. Competing hypotheses currently exist to explain the precise anesthetic mechanisms of VAs, but general disruption of membrane bound proteins, either selectively or en masse, is a common feature among favored models [2,3,4] In addition to their desired neurologic effects (e.g. analgesia, paralysis, amnesia, and sedation), VAs have a range of both beneficial and detrimental off-target effects in various organ systems, including immune modulation, tumor enhancement, and cardioprotection [5,6,7].
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