Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics
Julia Stokes,
Arielle Freed,
Rebecca Bornstein,
Kevin N Su,
John Snell,
Amanda Pan,
Grace X Sun,
Kyung Yeon Park,
Sangwook Jung,
Hailey Worstman,
Brittany M Johnson,
Philip G Morgan,
Margaret M Sedensky,
Simon C Johnson
Affiliations
Julia Stokes
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Arielle Freed
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States; University of Washington School of Dentistry, Seattle, United States
Rebecca Bornstein
Department of Pathology, University of Washington, Seattle, United States
Kevin N Su
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States
John Snell
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Amanda Pan
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Grace X Sun
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Kyung Yeon Park
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Sangwook Jung
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Hailey Worstman
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Brittany M Johnson
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States
Margaret M Sedensky
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States
Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States; Department of Pathology, University of Washington, Seattle, United States; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States; Department of Neurology, University of Washington, Seattle, United States
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.
