Strategies and experimental models for evaluating anesthetics: Effects on the developing nervous system
Strategies and experimental models for evaluating anesthetics: Effects on the developing nervous system
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DOI：
10.1213/ane.ob013e3181732c01
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发表时间：
2008-06-01
影响因子：
5.7
通讯作者：
Slikker, William
中科院分区：
文献类型：
--
作者：
Wang, Cheng;Slikker, William
儿科和产科外科的进步导致了需要麻醉的程序的持续时间和复杂性的增加。据报道，麻醉药物可引起发育中的大鼠脑内广泛的、剂量依赖性的细胞凋亡。非人灵长类动物的生理、药理、代谢和生殖系统与人类相似，特别是在怀孕期间，这使得猴子成为评估麻醉剂潜在神经毒性作用的特别好的动物模型。儿科麻醉药对这些神经元影响的脆弱窗口仅限于快速突触形成期，也被称为脑生长爆发期。为了最大限度地减少麻醉对儿童造成的风险，应解决以下问题：1.儿科麻醉实践中常用药物(吸入麻醉剂、咪达唑仑、氯胺酮和一氧化二氮)暴露与脑细胞丢失之间的关系是什么？2.是否存在“类别效应”，或者每种药物都需要单独考虑？3.用作麻醉剂的药物之间是否存在导致脑细胞死亡风险的重要相互作用？4.人类可能的脆弱时期是什么？药物基因组学/系统生物学方法在帮助促进对与大脑相关的生物过程的理解方面具有巨大的潜力。包括神经元的可塑性和神经毒性。由于发育神经毒性表现的复杂性和时间特征，药物基因组学/系统生物学方法可能被证明是增强我们对麻醉药诱导的生物学过程的理解的有用工具。因此，这篇综述的主要目的是描述这些方法和模型的应用，以及保护策略，特别是关于麻醉诱导的发育过程中神经细胞死亡的问题。下面的讨论大多基于氯胺酮的实验。这在一定程度上是由于在早期研究中使用了氯胺酮，以及使用这种药物进行了大量的临床前实验工作，以及在发育中的啮齿动物和非人类灵长类动物的麻醉研究中使用了氯胺酮。尽管氯胺酮在儿科麻醉中的应用相对有限，但研究结果足以值得关注N-甲基-D-天冬氨酸拮抗剂类药物。我们对氯胺酮的关注不应被解释为暗示与其他麻醉剂相比，氯胺酮引起神经变性的风险更大或更小。我们只是简单地描述我们拥有最多临床前数据的影响。
Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of procedures requiring anesthesia. It has been reported that anesthetic drugs cause widespread and dose-dependent apoptosis in the developing rat brain. The similarity of the physiology, pharmacology, metabolism, and reproductive systems of the nonhuman primate to that of the human especially during pregnancy, make the monkey an exceptionally good animal model for assessing potential neurotoxic effects of anesthetics. The window of vulnerability to these neuronal effects of pediatric anesthetics is restricted to the period of rapid synaptogenesis, also known as the brain growth spurt period. To minimize the risks to children resulting from the use of anesthesia, the following questions should be addressed:1. What is the relationship between exposure and brain cell loss for drugs commonly used in the practice of pediatric anesthesia (inhaled anesthetics, midazolam, ketamine, and nitrous oxide)?2. Are there "class effects," or does each drug need to be considered independently?3. Are there important interactions among the drugs used as anesthetics contributing to the risk of brain cell death?4. What is the likely period of human vulnerability?Pharmacogeneomic/system biology approaches have great potential for helping to advance the understanding of brain-related biological processes, including neuronal plasticity and neurotoxicity. Because of the complexity and temporal features of how developmental neurotoxicity is manifested, pharmacogenomic/systems biology approaches may prove to be useful tools for enhancing our understanding of the biological processes induced by anesthetics. Therefore, the main purpose of this review is to describe the application of these approaches and models, as well as protection strategies, especially as regards the issue of anesthetic-induced neuronal cell death during development.Much of the discussion that follows is based on experiments conducted with ketamine. This is due in part to the use of ketamine in the early studies and the volume of preclinical experimental work performed with this drug, as well as its use in anesthetic studies in developing rodents and nonhuman primates. Although ketamine use in pediatric anesthesia is relatively limited, the findings of the studies are sufficiently strong to merit concern about the N-methyl-D-aspartate antagonist drugs as a class. Our focus on ketamine should not be construed as implying that the risk of neurodegeneration with ketamine is greater, or less, than with other anesthetics. We are simply describing the effects where we have the most preclinical data.