Enhanced expression of peripheral benzodiazepine receptors in trimethyltin-exposed rat brain: a biomarker of neurotoxicity.
We have used the binding of the selective, high affinity, isoquinoline carboxamide, [3H]-PK11195, to measure the levels of Peripheral Benzodiazpine Receptors (PBR) in the brain of rats exposed to the well characterized neurotoxicant trimethyltin (TMT). The results demonstrate that autoradiograms of saggital sections of rats injected with a 8 mg/kg TMT dose, express a high level of [3H]-PK11195 binding in brain regions known to be damaged by TMT. The highest level of [3H]-PK11195 binding in the TMT-exposed rats occurred in the CA3/CA4 subfield of the hippocampus, followed by the primary olfactory cortex, the posteriomedial cortical amygdaloid nucleus, subiculum, and entorhinal cortex. These findings are consistent with the neuropathology of TMT in rats. The increase in [3H]-PK11195 binding in the brain of TMT-exposed rats was significant at 7 days after injection and remained elevated up to 42 days after exposure, the last time point measured in the study. This pattern is very similar to that observed for levels of the astrocyte intermediate filament protein, GFAP. The enhanced binding of [3H]-PK11195 in TMT-exposed rats was the result of a significant increase (p < 0.005) in the number of PBR with no change in affinity. The Bmax for [3H]-PK11195 binding in hippocampi from TMT-treated rats at 4 weeks post-injection was 606 +/- 25 (n = 4) fmoles/mg protein and 329 +/- 41 (n = 4) fmoles/mg protein for control. These findings suggest that the quantitative assessment of [3H]-PK11195 binding to PBR in the brain could represent a potential biomarker for assessing chemical-induced neurotoxicity. Since this ligand has been labeled with single photon (123I) or positron emitting (11C, 18F) radioisotopes, it can potentially be used with non-invasive imaging techniques such as Single Photon Emission Tomography (SPECT) or Positron Emission Tomography (PET) for human studies.
Guilarte
T R
TR
Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
Kuhlmann
A C
AC
O'Callaghan
J P
JP
Miceli
R C
RC
D000818:Animals; D001345:Autoradiography; D015415:Biomarkers; D001921:Brain / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D014298:Trimethyltin Compounds / Q000633:toxicity*
D015415:Biomarkers; D007546:Isoquinolines; D011963:Receptors, GABA-A; D014298:Trimethyltin Compounds; C046488:trimethyltin; C037850:PK 11195