Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
J Appl Toxicol. 2013 Jun;33(6):410-7. doi: 10.1002/jat.1751. Epub 2011 Nov 2.
Ketamine, a noncompetitive antagonist of N-methyl-d-aspartate-type glutamate receptors, is a pediatric anesthetic that has been shown to be neurotoxic in rodents and nonhuman primates when administered during the brain growth spurt. Recently, the zebrafish has become an attractive model for toxicity assays, in part because the predictive capability of the zebrafish model, with respect to chemical effects, compares well with that from mammalian models. In the transgenic (hb9:GFP) embryos used in this study, green fluorescent protein (GFP) is expressed in the motor neurons, facilitating the visualization and analysis of motor neuron development in vivo. In order to determine whether ketamine induces motor neuron toxicity in zebrafish, embryos of these transgenic fish were treated with different concentrations of ketamine (0.5 and 2.0 mm). For ketamine exposures lasting up to 20 h, larvae showed no gross morphological abnormalities. Analysis of GFP-expressing motor neurons in the live embryos, however, revealed that 2.0 mm ketamine adversely affected motor neuron axon length and decreased cranial and motor neuron populations. Quantitative reverse transcriptase-polymerase chain reaction analysis demonstrated that ketamine down-regulated the motor neuron-inducing zinc finger transcription factor Gli2b and the proneural gene NeuroD even at 0.5 mm concentration, while up-regulating the expression of the proneural gene Neurogenin1 (Ngn1). Expression of the neurogenic gene, Notch1a, was suppressed, indicating that neuronal precursor generation from uncommitted cells was favored. These results suggest that ketamine is neurotoxic to motor neurons in zebrafish and possibly affects the differentiating/differentiatedneurons rather than neuronal progenitors. Published 2011. This article is a US Government work and is in the public domain in the USA.
氯胺酮是一种非竞争性 N-甲基-D-天冬氨酸型谷氨酸受体拮抗剂，是一种儿科麻醉剂，当在大脑生长突增期间给予时，已在啮齿动物和非人灵长类动物中显示出神经毒性。最近，斑马鱼已成为毒性测定的一种有吸引力的模型，部分原因是斑马鱼模型在化学效应方面的预测能力与哺乳动物模型相当。在本研究中使用的转基因（hb9：GFP）胚胎中，绿色荧光蛋白（GFP）在运动神经元中表达，促进了体内运动神经元发育的可视化和分析。为了确定氯胺酮是否在斑马鱼中诱导运动神经元毒性，用不同浓度的氯胺酮（0.5 和 2.0 mM）处理这些转基因鱼的胚胎。对于持续长达 20 小时的氯胺酮暴露，幼虫没有表现出明显的形态异常。然而，对活体胚胎中表达 GFP 的运动神经元的分析表明，2.0 mM 氯胺酮会损害运动神经元轴突长度，并减少颅神经和运动神经元群体。定量逆转录聚合酶链反应分析表明，氯胺酮甚至在 0.5 mM 浓度下下调运动神经元诱导锌指转录因子 Gli2b 和神经原基因 NeuroD，同时上调神经原基因 Neurogenin1（Ngn1）的表达。神经发生基因 Notch1a 的表达受到抑制，表明从非定向细胞中产生神经元前体细胞受到青睐。这些结果表明，氯胺酮对斑马鱼的运动神经元具有神经毒性，并且可能影响正在分化/分化的神经元，而不是神经元前体。2011 年发表。本文是美国政府的工作，在美国属于公有领域。
