Potential neurotoxicity of ketamine in the developing rat brain.
Ketamine, an N-methyl-D-aspartate (NMDA) receptor ion channel blocker, is a widely used anesthetic recently reported to enhance neuronal death in developing rodents and nonhuman primates. This study evaluated dose-response and time-course effects of ketamine, levels of ketamine in plasma and brain, and the relationship between altered NMDA receptor expression and ketamine-induced neuronal cell death during development. Postnatal day 7 rats were administered 5, 10, or 20 mg/kg ketamine using single or multiple injections (subcutaneously) at 2-h intervals, and the potential neurotoxic effects were examined 6 h after the last injection. No significant neurotoxic effects were detected in layers II or III of the frontal cortex of rats administered one, three, or six injections of 5 or 10 mg/kg ketamine. However, in rats administered six injections of 20 mg/kg ketamine, a significant increase in the number of caspase-3- and Fluoro-Jade C-positive neuronal cells was observed in the frontal cortex. Electron microscopic observations showed typical nuclear condensation and fragmentation indicating enhanced apoptotic characteristics. Increased cell death was also apparent in other brain regions. In addition, apoptosis occurred after plasma and brain levels of ketamine had returned to baseline levels. In situ hybridization also showed a remarkable increase in mRNA signals for the NMDA NR1 subunit in the frontal cortex. These data demonstrate that ketamine administration results in a dose-related and exposure-time dependent increase in neuronal cell death during development. Ketamine-induced cell death appears to be apoptotic in nature and closely associated with enhanced NMDA receptor subunit mRNA expression.
Zou
Xiaoju
X
Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, Arkansas 72079, USA.
Patterson
Tucker A
TA
Sadovova
Natalya
N
Twaddle
Nathan C
NC
Doerge
Daniel R
DR
Zhang
Xuan
X
Fu
Xin
X
Hanig
Joseph P
JP
Paule
Merle G
MG
Slikker
William
W
Wang
Cheng
C
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D017403:In Situ Hybridization; D007649:Ketamine / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D011897:Random Allocation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D053148:Caspase 3