Positron emission tomography and functional characterization of a complete PBR/TSPO knockout
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Date
2014-11-19
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature
Abstract
The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer’s disease to anxiety. Here we show that global C57BL/6-Tspotm1GuWu(GuwiyangWurra)-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from GuwiyangWurraTSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of GuwiyangWurraTSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs. Copyright © 2014, Springer Nature
Description
Keywords
Positron computed tomography, Proteins, Translocation, Neurology, Drugs, Transgenic mice
Citation
Banati, R. B., Middleton, R. J., Chan, R., Hatty, C. R., Wai-Ying Kam, W., Quin, C., Graeber, M. B., Parmar, A., Zahra, D., Callaghan, P., Fok, S., Howell, N.,Grégoire , M., Szabo, A., Pham, T., Davis, E., & Liu, G. J. (2014). Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nature Communications, 5, 5452. doi:10.1038/ncomms6452