ToxSci Advance Access published online on January 6, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfn270
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Published by Oxford University Press 2009.
Potential Neurotoxicity of Ketamine in the Developing Rat Brain
a Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR 72079 USA b Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR 72079 USA c Toxicologic Pathology Associates, Jefferson, AR 72079 USA d Center for Devices and Radiological Health, U.S. Food & Drug Administration, Rockville, MD 20850 USA e Center for Drug Evaluation and Research, U.S. Food & Drug Administration, Silver Spring, MD 20993 USA
* Corresponding Author: Cheng Wang, MD., Ph.D, Division of Neurotoxicology, HFT-132, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR 72079-0502, USA Cheng.wang{at}fda.hhs.gov 870-543-7259 (voice) 870-543-7745 (fax)
Received October 23, 2008; revision received December 12, 2008; accepted December 12, 2008
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Abstract |
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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 (PND)-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 1, 3 or 6 injections of 5 or 10 mg/kg ketamine. However, in rats administered 6 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 (EM) 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.
Key Words: N-methyl-D-aspartate (NMDA) receptor; Neuronal cell death; Apoptosis.
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