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ToxSci Advance Access originally published online on February 24, 2006
Toxicological Sciences 2006 91(1):192-201; doi:10.1093/toxsci/kfj144
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Published by Oxford University Press 2006.

Blockade of N-Methyl-D-Aspartate Receptors by Ketamine Produces Loss of Postnatal Day 3 Monkey Frontal Cortical Neurons in Culture

Cheng Wang*,1, Natalya Sadovova{dagger}, Charlotte Hotchkiss{ddagger}, Xin Fu§, Andrew C. Scallet*, Tucker A. Patterson*, Joseph Hanig, Merle G. Paule* and William Slikker, Jr.*

* Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas; {dagger} Toxicologic Pathology Associates, Jefferson, Arkansas; {ddagger} The Bionetics Corporation, Jefferson, Arkansas; § Division of Biochemical Toxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas; and Center for Drug Evaluation and Research/Food and Drug Administration, Rockville, Maryland

Received January 5, 2006; accepted February 13, 2006

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used as a general pediatric anesthetic. Recent data suggest that anesthetic drugs may cause neurodegeneration during development. The purpose of this study was to determine the robustness of ketamine-induced developmental neurotoxicity using rhesus monkey frontal cortical cultures and also to determine if dysregulation of NMDA receptor subunits promotes ketamine-induced cell death. Frontal cortical cells collected from the neonatal monkey were incubated for 24 h with 1, 10, or 20µM ketamine alone or with ketamine plus either NR1 antisense oligonucleotides or the nuclear factor kB translocation inhibitor, SN-50. Ketamine caused a marked reduction in the neuronal marker polysialic acid neural cell adhesion molecule and mitochondrial metabolism, as well as an increase in DNA fragmentation and release of lactate dehydrogenase. Ketamine-induced effects were blocked by NR1 antisenses and SN-50. These data suggest that NR1 antisenses and SN-50 offer neuroprotection from the enhanced degeneration induced by ketamine in vitro.

Key Words: NMDA receptor; ketamine; antisense oligonucleotide; neurodegeneration; in vitro; neonatal rhesus monkey.


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