Division of Systems Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
Neuroscience. 2010 Mar 31;166(3):852-63. doi: 10.1016/j.neuroscience.2010.01.007. Epub 2010 Jan 18.
Ketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with accelerated neuronal apoptosis in the developing rodent brain. In this study, postnatal day (PND) 7 rats were treated with 20 mg/kg ketamine or saline in six successive doses (s.c.) at 2-h intervals. Brain frontal cortical areas were collected 6 h after the last dose and RNA isolated and hybridized to Illumina Rat Ref-12 Expression BeadChips containing 22,226 probes. Many of the differentially expressed genes were associated with cell death or differentiation and receptor activity. Ingenuity Pathway Analysis software identified perturbations in NMDA-type glutamate, GABA and dopamine receptor signaling. Quantitative polymerase chain reaction (Q-PCR) confirmed that NMDA receptor subunits were significantly up-regulated. Up-regulation of NMDA receptor mRNA signaling was further confirmed by in situ hybridization. These observations support our working hypothesis that prolonged ketamine exposure produces up-regulation of NMDA receptors and subsequent over-stimulation of the glutamatergic system by endogenous glutamate, triggering enhanced apoptosis in developing neurons.
氯胺酮是一种非竞争性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，与发育中啮齿动物大脑中的神经元凋亡加速有关。在这项研究中，将出生后第 7 天（PND）的大鼠用 20mg/kg 氯胺酮或生理盐水以 2 小时的间隔连续 6 次（sc）处理。最后一次给药后 6 小时收集大脑额皮质区，并分离 RNA 并与包含 22226 个探针的 Illumina Rat Ref-12 Expression BeadChips 杂交。许多差异表达的基因与细胞死亡或分化和受体活性有关。Ingenuity Pathway Analysis 软件确定了 NMDA 型谷氨酸、GABA 和多巴胺受体信号的干扰。定量聚合酶链反应（Q-PCR）证实 NMDA 受体亚基显著上调。原位杂交进一步证实了 NMDA 受体 mRNA 信号的上调。这些观察结果支持我们的工作假设，即长时间暴露于氯胺酮会导致 NMDA 受体上调，随后内源性谷氨酸过度刺激谷氨酸能系统，导致发育中的神经元凋亡增强。
