ToxSci Advance Access published online on April 10, 2007
Toxicological Sciences, 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, 3900 NCTR Rd., Jefferson, AR 72079, USA
Bionetics Corporation, 3900 NCTR Rd., Jefferson, AR 72079, USA
Toxicologic Pathology Associates, 3900 NCTR Rd., Jefferson, AR 72079, USA
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, 3900 NCTR Rd., Jefferson, AR 72079, USA
¶ Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, U.S. Food & Drug Administration, White Oak Life Sciences Building 64, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA
1 To whom correspondence should be addressed at the National Center for Toxicological Research, HFT-1, Food & Drug Administration, Jefferson, AR 72079-0502. Phone: (870) 543-7517. Fax: (870) 543-7576. E-mail: william.slikker{at}fda.hhs.gov
Received February 15, 2007; revision received March 22, 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) were administered ketamine intravenously for 24 hours to maintain a surgical anesthetic plane, followed by a 6-hour withdrawal period. Similar studies were performed in postnatal day 5 animals with 3 hours of ketamine anesthesia. Animals were subsequently perfused and brain tissue processed for analyses. Ketamine (24-hr 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 postnatal day 5 animals but not in postnatal day 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 NMDA receptor NR1 subunit mRNA in the frontal cortex where enhanced cell death was apparent. Earlier developmental stages (122 days of gestation and 5 postnatal days) appear more sensitive to ketamine-induced neuronal cell death than later in development (35 postnatal days). However, a shorter duration of ketamine anesthesia (3-hr) 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.
William Slikker, Jr. (william.slikker{at}fda.hhs.gov), Xiaoju Zou (xiaoju.zou{at}fda.hhs.gov), Charlotte E. Hotchkiss (charlotte.hotchkiss{at}fda.hhs.gov), Rebecca L. Divine (becky.divine{at}fda.hhs.gov), Natalya Sadovova (natalya.sadovova{at}fda.hhs.gov), Nathan C. Twaddle (nathan.twaddle{at}fda.hhs.gov), Daniel R. Doerge (daniel.doerge{at}fda.hhs.gov), Andrew C. Scallet (andrew.scallet{at}fda.hhs.gov), Tucker A. Patterson (tucker.patterson{at}fda.hhs.gov), Joseph P. Hanig (joseph.hanig{at}fda.hhs.gov), Merle G. Paule (merle.paule{at}fda.hhs.gov), Cheng Wang (cheng.wang{at}fda.hhs.gov)
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