Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Stokes, J.; Freed, A.; Pan, A.; Sun, G. X.; Bornstein, R.; Snell, J.; Park, K. Y.; Morgan, P. G.; Sedensky, M. M.; Johnson, S. C.

doi:10.1101/2020.12.08.415950

bioRxiv · 10.1101/2020.12.08.415950

Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Stokes, J.·Freed, A.·Pan, A.·Sun, G. X.·Bornstein, R.·Snell, J.·Park, K. Y.·Morgan, P. G.·Sedensky, M. M.·Johnson, S. C.

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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 {beta}-hydroxybutarate ({beta}-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. {beta}-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of {beta}-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.

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Stokes, J., Freed, A., Pan, A., Sun, G. X., Bornstein, R., Snell, J., Park, K. Y., Morgan, P. G., Sedensky, M. M., Johnson, S. C.. 2020-12-09. Mechanisms underlying neonate specific metabolic effects of volatile anesthetics. https://doi.org/10.1101/2020.12.08.415950

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