Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics

eLife

Grace X Sun¹  Sangwook Jung¹  Amanda Pan¹  Julia Stokes¹  Hailey Worstman¹  John Snell¹  Kyung Yeon Park¹  Brittany M Johnson¹  Margaret M Sedensky²  Philip G Morgan²  Simon C Johnson³  Arielle Freed⁴  Kevin N Su⁵  Rebecca Bornstein⁶ 

[1] 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;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;Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, United States;University of Washington School of Dentistry, Seattle, United States;Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, United States;Department of Pathology, University of Washington, Seattle, United States;

关键词: anesthesia;    fatty acid oxidation;    mitochondria;    neonate;    metabolism;    ketogenesis;    Mouse;   

DOI  :  10.7554/eLife.65400

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY