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挥发性麻醉剂对新生儿产生特殊代谢作用的机制。

Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics.

机构信息

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.

University of Washington School of Dentistry, Seattle, United States.

出版信息

Elife. 2021 Jul 13;10:e65400. doi: 10.7554/eLife.65400.

DOI:10.7554/eLife.65400
PMID:34254587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8291971/
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.

摘要

挥发性麻醉剂（VAs）在医学中被广泛应用，但它们作用的机制仍不清楚。尽管常规麻醉在健康个体中是安全的，但已记录了许多过敏反应的实例，并且人们非常关注 VAs 对新生儿大脑发育的影响。有证据表明，VAs 有多个靶点，麻醉和非麻醉作用由神经受体、离子通道和线粒体电子传递链介导。在这里，我们描述了 VAs 在新生小鼠中一种意想不到的代谢作用。在低于麻醉所需浓度的情况下，新生小鼠血液中的β-羟基丁酸（β-HB）会迅速被 VAs 消耗殆尽。而成年动物（包括处于生酮饮食的动物）的β-HB 不受影响。β-HB 的消耗是由柠檬酸积累、乙酰辅酶 A 羧化酶产生丙二酰辅酶 A以及抑制脂肪酸氧化介导的。成年动物的柠檬酸和丙二酰辅酶 A 也会发生类似的显著变化，但对丙二酰辅酶 A 不敏感，与年轻动物相比，代谢灵活性降低。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ef4/8291971/36bf5e7610aa/elife-65400-fig5-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ef4/8291971/2f62dc42063e/elife-65400-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ef4/8291971/f64ff6d91b20/elife-65400-fig1-figsupp2.jpg
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