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

Journal Article


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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 GuwiyangWurra​TSPO 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 GuwiyangWurra​TSPO 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.

Authors


  •   Zahra, David (external author)
  •   Liu, Guo Jun (external author)
  •   Middleton, Ryan J. (external author)
  •   Chan, Ronal (external author)
  •   Hatty, Claire R. (external author)
  •   Kam, Winnie Wai-Ying (external author)
  •   Quin, Candice (external author)
  •   Callaghan, Paul (external author)
  •   Fok, Sandra (external author)
  •   Howell, Nicholas R. (external author)
  •   Davis, Emma (external author)
  •   Pham, Tien Q. (external author)
  •   Szabo, Alexander M. (external author)
  •   Gregoire, Marie-Claude (external author)
  •   Parmar, Arvind (external author)
  •   Graeber, Manuel B. (external author)
  •   Banati, Richard B.

Publication Date


  • 2014

Citation


  • Banati, R. B., Middleton, R. J., Chan, R., Hatty, C. R., Kam, W., Quin, C., Graeber, M. B., Parmar, A., Zahra, D., Callaghan, P., Fok, S., Howell, N. R., Gregoire, M., Szabo, A., Pham, T., Davis, E. & Liu, G. (2014). Positron emission tomography and functional characterization of a complete ​PBR/​TSPO knockout. Nature Communications, 5 1-12.

Scopus Eid


  • 2-s2.0-84923241444

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4848&context=eispapers

Ro Metadata Url


  • http://ro.uow.edu.au/eispapers/3829

Has Global Citation Frequency


Number Of Pages


  • 11

Start Page


  • 1

End Page


  • 12

Volume


  • 5

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 GuwiyangWurra​TSPO 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 GuwiyangWurra​TSPO 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.

Authors


  •   Zahra, David (external author)
  •   Liu, Guo Jun (external author)
  •   Middleton, Ryan J. (external author)
  •   Chan, Ronal (external author)
  •   Hatty, Claire R. (external author)
  •   Kam, Winnie Wai-Ying (external author)
  •   Quin, Candice (external author)
  •   Callaghan, Paul (external author)
  •   Fok, Sandra (external author)
  •   Howell, Nicholas R. (external author)
  •   Davis, Emma (external author)
  •   Pham, Tien Q. (external author)
  •   Szabo, Alexander M. (external author)
  •   Gregoire, Marie-Claude (external author)
  •   Parmar, Arvind (external author)
  •   Graeber, Manuel B. (external author)
  •   Banati, Richard B.

Publication Date


  • 2014

Citation


  • Banati, R. B., Middleton, R. J., Chan, R., Hatty, C. R., Kam, W., Quin, C., Graeber, M. B., Parmar, A., Zahra, D., Callaghan, P., Fok, S., Howell, N. R., Gregoire, M., Szabo, A., Pham, T., Davis, E. & Liu, G. (2014). Positron emission tomography and functional characterization of a complete ​PBR/​TSPO knockout. Nature Communications, 5 1-12.

Scopus Eid


  • 2-s2.0-84923241444

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4848&context=eispapers

Ro Metadata Url


  • http://ro.uow.edu.au/eispapers/3829

Has Global Citation Frequency


Number Of Pages


  • 11

Start Page


  • 1

End Page


  • 12

Volume


  • 5