Positron emission tomography and functional characterization of a complete PBR/TSPO knockout

Richard B. Banati (), Ryan J. Middleton, Ronald Chan, Claire R. Hatty, Winnie Wai-Ying Kam, Candice Quin, Manuel B. Graeber, Arvind Parmar, David Zahra, Paul Callaghan, Sandra Fok, Nicholas R. Howell, Marie Gregoire, Alexander Szabo, Tien Pham, Emma Davis and Guo-Jun Liu ()
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Richard B. Banati: Life Sciences, Australian Nuclear Science and Technology Organisation
Ryan J. Middleton: Life Sciences, Australian Nuclear Science and Technology Organisation
Ronald Chan: Brain & Mind Research Institute, The University of Sydney
Claire R. Hatty: Brain & Mind Research Institute, The University of Sydney
Winnie Wai-Ying Kam: Life Sciences, Australian Nuclear Science and Technology Organisation
Candice Quin: Brain & Mind Research Institute, The University of Sydney
Manuel B. Graeber: Brain & Mind Research Institute, The University of Sydney
Arvind Parmar: Life Sciences, Australian Nuclear Science and Technology Organisation
David Zahra: Life Sciences, Australian Nuclear Science and Technology Organisation
Paul Callaghan: Life Sciences, Australian Nuclear Science and Technology Organisation
Sandra Fok: Brain & Mind Research Institute, The University of Sydney
Nicholas R. Howell: Life Sciences, Australian Nuclear Science and Technology Organisation
Marie Gregoire: Life Sciences, Australian Nuclear Science and Technology Organisation
Alexander Szabo: Life Sciences, Australian Nuclear Science and Technology Organisation
Tien Pham: Life Sciences, Australian Nuclear Science and Technology Organisation
Emma Davis: Life Sciences, Australian Nuclear Science and Technology Organisation
Guo-Jun Liu: Life Sciences, Australian Nuclear Science and Technology Organisation

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6452

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