Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair

Abstract

For over 15 years, the peripheral benzodiazepine receptor (PBR), recently named translocator protein 18 kDa (TSPO) has been studied as a biomarker of reactive gliosis and inflammation associated with a variety of neuropathological conditions. Early studies documented that in the brain parenchyma, TSPO is exclusively localized in glial cells. Under normal physiological conditions, TSPO levels are low in the brain neuropil but they markedly increase at sites of brain injury and inflammation making it uniquely suited for assessing active gliosis. This research has generated significant efforts from multiple research groups throughout the world to apply TSPO as a marker of "active" brain pathology using in vivo imaging modalities such as Positron Emission Tomography (PET) in experimental animals and humans. Further, in the last few years, there has been an increased interest in understanding the molecular and cellular function(s) of TSPO in glial cells. The latest evidence suggests that TSPO may not only serve as a biomarker of active brain disease but also the use of TSPO-specific ligands may have therapeutic implications in brain injury and repair. This review presents an overview of the history and function of TSPO focusing on studies related to its use as a sensor of active brain disease in experimental animals and in human studies.

Figure 1

Schematic of TSPO and associated proteins. Published with permission from Elsevier Limited. Taken from Papadopoulos et al., TIPS 27: 402–409, 2006.

Figure 2

Pseudocolor images of [³H]-R-PK11195 binding to TSPO in rodent brain. Color in images represents levels of [³H]-R-PK11195 binding with blue representing low levels, green-yellow representative of intermediate levels, and red high levels of binding. Panels A, D, F are pseudocolor images from control animals and B, C, E, G are from animals treated with different neurotoxicants. Panels B and C represent levels of TSPO following a single injection (8 mg/kg) of the neurotoxicant trimethyltin. Panel B represents levels of TSPO at 14 days after TMT administration and panel C after 6 weeks following TMT administration. There is a dramatic increase in hippocampal regions and piriform cortex at 14 days with a marked increase in different hippocampal regions at 6 weeks. See progressive increase in the thalamus. Panel E is representative of an animal that had a seizure after domoic acid administration (3 mg/kg). Compare image in E to control in D. Panel G represents a mouse that had been administered cuprizone in the diet for 4 weeks. Increased levels of TSPO are noted in the dorsal hippocampal commisure and in the hippocampus proper, two brain regions that are known to develop dmyelination in this model. D3V = dorsal third ventricle; 3V = third ventricle; LV = lateral ventricle; Th = thalamus; PC = piriform cortex; CA4 = CA4 region of the hippocampus; CA3 = CA3 region of the hippocampus; CA1 = CA1 region of the hippocampus; Ctx = cerebral cortex; Cb = cerebellum; hipp = hippocampus; cc = corpus callosum; dhc = dorsal hippocampal commisure.

Figure 3

Scatchard analysis of [³H]-R-PK11195 binding to TSPO in the cerebral cortex of animals exposed to cuprizone for 4 weeks. The data clearly show that the effect of cuprizone treatment on [³H]-R-PK11195 specific binding is in the maximal number of binding sies (Bmax) and not in the affinity (Kd). Published with permission from Oxford University Press. Taken from Chen et al., Brain 127: 1379–1392, 2004.