ToxSci Advance Access originally published online on July 14, 2004
Toxicological Sciences 2004 81(2):364-370; doi:10.1093/toxsci/kfh224
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Toxicological Sciences vol. 81 no. 2 © Society of Toxicology 2004; all rights reserved.
Developmental Neurotoxicity of Ketamine: Morphometric Confirmation, Exposure Parameters, and Multiple Fluorescent Labeling of Apoptotic Neurons
* Division of Neurotoxicology, NCTR/FDA, Jefferson, Arkansas 72079; USUHS, Bethesda, Maryland 20892; CDER/FDA, Silver Spring, Maryland 20993; and NIDA/NIH, Bethesda, Maryland 20892
Received May 27, 2004; accepted July 9, 2004
Ketamine is a widely used pediatric anesthetic recently reported (C. Ikonomidou et al., 1999, Science 283, 70–74) to enhance neuronal death in neonatal rats. To confirm and extend these results, we treated four groups of PND 7 rats with seven sc doses, one every 90 min, of either saline, 10 mg/kg ketamine, 20 mg/kg ketamine, or a single dose of 20 mg/kg ketamine. The repeated doses of 20 mg/kg ketamine increased the number of silver-positive (degenerating) neurons in the dorsolateral thalamus to a degree comparable to previous results (Ikonomidou et al., 1999, Science 283, 70–74), i.e., 28-fold vs. 31-fold respectively. However, blood levels of ketamine immediately after the repeated 20 mg/kg doses were about 14 µg/ml, about seven-fold greater than anesthetic blood levels in humans (J. M. Malinovsky et al., 1996, Br. J. Anaesth. 77, 203–207; R. A. Mueller and R. Hunt, 1998, Pharmacol. Biochem. Behav. 60, 15–22). Levels of ketamine in blood following exposure to the multiple 10 mg/kg doses of ketamine or to a single 20 mg/kg dose ranged around 2–5 µg/ml; although these blood levels are close to an anesthetic level in humans, they failed to produce neurodegeneration. To investigate the mode of ketamine-induced neuronal death, coronal sections were stained with both Fluoro-Jade B (a green fluorescent stain selective for neurodegeneration) and DAPI (a blue DNA stain), as well as for caspase-3 (using an antisera labeled red with rhodamine). These histochemical results confirmed the developmental neurotoxicity of ketamine, demonstrated that Fluoro-Jade B (FJ-B), like silver methods, successfully stained degenerating neurons in neonatal rats, and indicated that ketamine acts by increasing the rate of neuronal apoptosis.
Key Words: neurodegeneration; apoptosis; blood levels; anesthesia; NMDA; caspase-3.
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