title: Ketamine-induced neuronal cell death in the perinatal rhesus monkey.
abstract: 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.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079-0502, USA. william.slikker@fda.hhs.gov
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Zou
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Hotchkiss
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Divine
authors.forename: Natalya
authors.initials: N
authors.lastname: Sadovova
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Twaddle
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Scallet
authors.forename: Tucker A
authors.initials: TA
authors.lastname: Patterson
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
mesh_terms: D000778:Anesthetics, Dissociative / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001345:Autoradiography; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005452:Fluoresceins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007649:Ketamine / Q000493:pharmacokinetics / Q000633:toxicity*; D008253:Macaca mulatta; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects*; D009930:Organic Chemicals; D010092:Oximetry; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012015:Reference Standards; D016622:Silver Staining
chemical_list: D000778:Anesthetics, Dissociative; D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; D009930:Organic Chemicals; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C435731:fluoro jade; D007649:Ketamine; D053148:Caspase 3