Potential Neurotoxicity of Ketamine in the Developing Rat Brain
Potential Neurotoxicity of Ketamine in the Developing Rat Brain
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DOI：
10.1093/toxsci/kfn270
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发表时间：
2009-03-01
影响因子：
3.8
通讯作者：
Wang, Cheng
中科院分区：
文献类型：
--
作者：
Zou, Xiaoju;Patterson, Tucker A.;Wang, Cheng
氯胺酮是一种N-甲基-D-天冬氨酸（NMDA）受体离子通道阻滞剂，是一种广泛使用的麻醉剂，最近报道可增强发育中啮齿动物和非人灵长类动物的神经元死亡。本研究评价了氯胺酮的剂量反应和时程效应、血浆和脑中氯胺酮的水平以及发育过程中NMDA受体表达改变与氯胺酮诱导的神经元细胞死亡之间的关系。出生后第7天，以2 h间隔单次或多次注射（皮下）给予大鼠5、10或20 mg/kg氯胺酮，并在末次注射后6 h检查潜在神经毒性作用。在注射1次、3次或6次5或10 mg/kg氯胺酮的大鼠额叶皮层第II层或第III层中未检测到显著的神经毒性作用。然而，在6次注射20 mg/kg氯胺酮的大鼠中，在额叶皮质中观察到半胱天冬酶-3和Fluoro-Jade C阳性神经元细胞数量显著增加。电子显微镜观察显示典型的核浓缩和碎裂，表明增强的凋亡特征。在其他大脑区域，细胞死亡的增加也很明显。此外，在氯胺酮的血浆和脑水平恢复至基线水平后发生细胞凋亡。原位杂交也表明，在额叶皮层的NMDA NR 1亚基的mRNA信号显着增加。这些数据表明，氯胺酮给药导致发育期间神经元细胞死亡的剂量相关性和时间依赖性增加。氯胺酮诱导的细胞死亡似乎是凋亡的性质，并与NMDA受体亚基mRNA表达增强密切相关。
Ketamine, an N-methyl-D-aspartate (NMDA) receptor ion channel blocker, is a widely used anesthetic recently reported to enhance neuronal death in developing rodents and nonhuman primates. This study evaluated dose-response and time-course effects of ketamine, levels of ketamine in plasma and brain, and the relationship between altered NMDA receptor expression and ketamine-induced neuronal cell death during development. Postnatal day 7 rats were administered 5, 10, or 20 mg/kg ketamine using single or multiple injections (subcutaneously) at 2-h intervals, and the potential neurotoxic effects were examined 6 h after the last injection. No significant neurotoxic effects were detected in layers II or III of the frontal cortex of rats administered one, three, or six injections of 5 or 10 mg/kg ketamine. However, in rats administered six injections of 20 mg/kg ketamine, a significant increase in the number of caspase-3- and Fluoro-Jade C-positive neuronal cells was observed in the frontal cortex. Electron microscopic observations showed typical nuclear condensation and fragmentation indicating enhanced apoptotic characteristics. Increased cell death was also apparent in other brain regions. In addition, apoptosis occurred after plasma and brain levels of ketamine had returned to baseline levels. In situ hybridization also showed a remarkable increase in mRNA signals for the NMDA NR1 subunit in the frontal cortex. These data demonstrate that ketamine administration results in a dose-related and exposure-time dependent increase in neuronal cell death during development. Ketamine-induced cell death appears to be apoptotic in nature and closely associated with enhanced NMDA receptor subunit mRNA expression.