Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture.
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 20 microM 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.
Wang
Cheng
C
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas 72079-0502, USA. cheng.wang@fda.hhs.gov
Sadovova
Natalya
N
Hotchkiss
Charlotte
C
Fu
Xin
X
Scallet
Andrew C
AC
Patterson
Tucker A
TA
Hanig
Joseph
J
Paule
Merle G
MG
Slikker
William
W
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D017931:DNA Primers; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007649:Ketamine / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D017931:DNA Primers; D018691:Excitatory Amino Acid Antagonists; D016328:NF-kappa B; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine