MicroPET imaging of ketamine-induced neuronal apoptosis with radiolabeled DFNSH.
Recent reports indicate that 6-12 h of ketamine anesthesia can trigger neuronal apoptosis in postnatal day (PND) 7 rats. In vitro, ex vivo, and confocal fluorescent imaging studies suggest that dansyl compounds can accumulate within the cytoplasm of the apoptotic cell. High-resolution positron emission tomography (microPET) imaging has been proposed as a minimally invasive method for detecting apoptosis in the rat brain. Compared with [(18)F]-labeled annexin V, which binds to externalized phosphatidylserine (PS) on the outer membrane of apoptotic cells, intracellular uptake of the dansylhydrazone of p-fluorobenzaldehyde (DFNSH) may lead to improved target-to-background contrast ratios. In this study, the effect of ketamine on the uptake and retention of [(18)F]-DFNSH in the rat brain was investigated using microPET imaging. On PND 7, rat pups in the experimental group were exposed, at 2-h intervals, to six subcutaneous injections of ketamine (20 mg/kg) and control rat pups received six injections of saline. On PND 35, [(18)F]-DFNSH (37 MBq) was injected into the tail vein of rats and microPET images were obtained over 2 h following the injection. Radiolabeled tracer accumulation in the region of interest (ROI) in the frontal cortex was converted into standard uptake values (SUVs). The radiotracer was quickly distributed into the brains of both ketamine- and saline-treated rats. Compared with the control group, the uptake of [(18)F]-DFNSH was significantly increased in the ROI, frontal cortex area of ketamine-treated rats. In addition, the wash-out duration of the tracer was prolonged in the ketamine-treated animals. This study demonstrates that microPET imaging is capable of distinguishing differences in retention of [(18)F]-DFNSH in ROI and suggests that this compound may serve as a minimally invasive biomarker of neuronal apoptosis in rodents.
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079-9502, USA.
X
X
Zhang
M G
MG
Paule
G D
GD
Newport
N
N
Sadovova
M S
MS
Berridge
S M
SM
Apana
G
G
Kabalka
W
W
Miao
W
W
Slikker
Cheng
C
Wang
D000778:Anesthetics, Dissociative / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001547:Benzaldehydes / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000778:Anesthetics, Dissociative; D001547:Benzaldehydes; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D007649:Ketamine