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ToxSci Advance Access published online on February 24, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj144
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Published by Oxford University Press 2006.
Received January 5, 2006
Accepted February 13, 2006

Neurotoxicology

Blockade of N-Methyl-D-Aspartate (NMDA) Receptors by Ketamine Produces Loss of Postnatal Day 3 (PND-3) Monkey Frontalcortical Neurons in Culture

C. Wang 1 *, N. Sadovova 2, C. Hotchkiss 3, X. Fu 4, A.C. Scallet 1, T.A. Patterson 1, J. Hanig 5, M.G. Paule 1, and W. Slikker Jr. 1

1 Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR
2 Toxicologic Pathology Associates, Jefferson, AR
3 The Bionetics Corporation, Jefferson, AR
4 Division of Biochemical Toxicology, National Center for Toxicological Research/FDA, Jefferson, AR
5 Center for Drug Evaluation and Research/FDA, Rockville, MD

* To whom correspondence should be addressed.
C. Wang, E-mail: cwang{at}nctr.fda.gov


  Abstract

Ketamine, an 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 hrs with 1, 10 or 20 µM ketamine alone or with ketamine plus either NR1 antisense oligonucleotides or the NF-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 enhanced degeneration induced by ketamine in vitro.

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