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ToxSci Advance Access published online on July 14, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh224
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received May 27, 2004
Accepted July 9, 2004

Neurotoxicology

Developmental Neurotoxicity of Ketamine: Morphometric Confirmation, Exposure Parameters, and Multiple Fluorescent Labeling of Apoptotic Neurons

A. C. Scallet 1*, L. C. Schmued 1, W. Slikker Jr.1, N. Grunberg 2, P. J. Faustino 3, H. Davis 4, D. Lester 3, P. S. Pine 3, F. Sistare 3, J. P. Hanig 3

1 Division of Neurotoxicology, NCTR/FDA, Jefferson, AR 72079
2 USUHS, Bethesda, MD 20892
3 CDER/FDA, Silver Spring, MD 20993
4 NIDA/NIH, Bethesda, MD 20892

* To whom correspondence should be addressed. E-mail: AScallet{at}nctr.fda.gov.


  Abstract

Ketamine is a widely used pediatric anesthetic recently reported (Ikonomidou et al., 1999) to enhance neuronal death in neonatal rats. To confirm and extend these results, we treated 4 groups of PND7 rats with 7 subcutaneous doses, one every 90 minutes, 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), 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 7-fold greater than anesthetic blood levels in humans (Malinovsky et al., 1996; Mueller and Hunt, 1998). 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 FJ-B, like silver methods, successfully stained degenerating neurons in neonatal rats, and indicated that ketamine acts by increasing the rate of neuronal apoptosis.

Keywords: Neurodegeneration; Apoptosis; Blood Levels; Anesthesia; NMDA; Caspase-3.
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