ToxSci Advance Access originally published online on April 10, 2007
Toxicological Sciences 2007 98(1):145-158; doi:10.1093/toxsci/kfm084
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Published by Oxford University Press 2007.
Ketamine-Induced Neuronal Cell Death in the Perinatal Rhesus Monkey
* Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food & Drug Administration
Bionetics Corporation
Toxicologic Pathology Associates
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, Arkansas 72079
¶ Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, U.S. Food & Drug Administration, Silver Spring, Maryland 20993
1 To whom correspondence should be addressed at National Center for Toxicological Research, HFT-1, Food & Drug Administration, Jefferson, AR 72079-0502. Fax: (870) 543-7576. E-mail: william.slikker{at}fda.hhs.gov.
Received February 15, 2007; accepted March 23, 2007
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Abstract |
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Ketamine is widely used as a pediatric anesthetic. Studies in developing rodents have indicated that ketamine-induced anesthesia results in brain cell death. Additional studies are needed to determine if ketamine anesthesia results in brain cell death in the nonhuman primate and if so, to begin to define the stage of development and the duration of ketamine anesthesia necessary to produce brain cell death. Rhesus monkeys (N = 3 for each treatment and control group) at three stages of development (122 days of gestation and 5 and 35 postnatal days [PNDs]) were administered ketamine intravenously for 24 h to maintain a surgical anesthetic plane, followed by a 6-h withdrawal period. Similar studies were performed in PND 5 animals with 3 h of ketamine anesthesia. Animals were subsequently perfused and brain tissue processed for analyses. Ketamine (24-h infusion) produced a significant increase in the number of caspase 3–, Fluoro-Jade C– and silver stain–positive cells in the cortex of gestational and PND 5 animals but not in PND 35 animals. Electron microscopy indicated typical nuclear condensation and fragmentation in some neuronal cells, and cell body swelling was observed in others indicating that ketamine-induced neuronal cell death is most likely both apoptotic and necrotic in nature. Ketamine increased N-methyl-D-aspartate (NMDA) receptor NR1 subunit messenger RNA in the frontal cortex where enhanced cell death was apparent. Earlier developmental stages (122 days of gestation and 5 PNDs) appear more sensitive to ketamine-induced neuronal cell death than later in development (35 PNDs). However, a shorter duration of ketamine anesthesia (3 h) did not result in neuronal cell death in the 5-day-old monkey.
Key Words: NMDA receptor; ketamine; neurotoxicology; apoptosis; development; anesthetic agents; nonhuman primate.
Disclaimer: This document has been reviewed in accordance with U.S. FDA policy and approved for publication. Approval does not signify that the contents necessarily reflect the position or opinions of the FDA nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA.
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