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ToxSci Advance Access originally published online on July 28, 2009
Toxicological Sciences 2009 111(2):355-361; doi:10.1093/toxsci/kfp167
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Published by Oxford University Press 2009.

A Minimally Invasive, Translational Biomarker of Ketamine-Induced Neuronal Death in Rats: microPET Imaging Using 18F-Annexin V

Xuan Zhang*, Merle G. Paule*, Glenn D. Newport*, Xiaoju Zou*, Natalya Sadovova{dagger}, Marc S. Berridge{ddagger}, Scott M. Apana{ddagger}, Joseph P. Hanig§, William Slikker, Jr* and Cheng Wang*,1

* Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079 {dagger} Toxicologic Pathology Associates, Jefferson, Arkansas 72079 {ddagger} 3D Imaging, LLC, Little Rock, Arkansas 72113 § Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993

1 To whom correspondence should be addressed at Division of Neurotoxicology, National Center for Toxicological Research/U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079-9502. Fax: (870) 543-7745. E-mail: cheng.wang{at}fda.hhs.gov.

Received June 4, 2009; accepted July 16, 2009


  Abstract

It has been reported that suppression of N-methyl-D-aspartate (NMDA) receptor function by ketamine may trigger apoptosis of neurons when given repeatedly during the brain growth spurt period. Because microPET scans can provide in vivo molecular imaging at sufficient resolution, it has been proposed as a minimally invasive method for detecting apoptosis using the tracer 18F-labeled annexin V. In this study, the effect of ketamine on the metabolism and integrity of the rat brain were evaluated by investigating the uptake and retention of 18F-fluorodeoxyglucose (FDG) and 18F-annexin V using microPET imaging. On postnatal day (PND) 7, rat pups in the experimental group were exposed to six injections of ketamine (20 mg/kg at 2-h intervals) and control rat pups received six injections of saline. On PND 35, 37 MBq (1 mCi) of 18F-FDG or 18F-annexin V was injected into the tail vein of treated and control rats, and static microPET images were obtained over 1 (FDG) and 2 h (annexin V) following the injection. No significant difference was found in 18F-FDG uptake in the regions of interest (ROIs) in the brains of ketamine-treated rats compared with saline-treated controls. The uptake of 18F-annexin V, however, was significantly increased in the ROI of ketamine-treated rats. Additionally, the duration of annexin V tracer washout was prolonged in the ketamine-treated animals. These results demonstrate that microPET imaging is capable of distinguishing differences in retention of 18F-annexin V in different brain regions and suggests that this approach may provide a minimally invasive biomarker of neuronal apoptosis in rats.

Key Words: ketamine; apoptosis; microPET.


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