Imaging the glial peripheral benzodiazepine receptor (translocator protein 18 kDa) response as a marker of brain injury/inflammation

The peripheral benzodiazepine receptor (PBR) or translocator protein (18kDa) (TSPO) is exclusively located in glial cells in the central nervous system (CNS) and has been investigated as a sensitive marker of reactive gliosis and inflammation associated with neuropathological conditions.; We used a murine model of cuprizone-induced demyelination to broaden the application of TSPO as a marker of brain injury and to validate the relationship between TSPO levels and glial cell types. Our findings indicate that brain TSPO levels increased as a function of dose and duration of cuprizone treatment and it was detectable prior to observable demyelination. Increased TSPO levels were associated with the degree of demyelination and temporal activation of glial cell types. Emulsion autoradiography of [3H]-(R)-PK11195 binding to TSPO coupled with immunohistochemistry confirmed that increased TSPO levels co-localized to both microglia and astrocytes.; We also examined TSPO response during remyelination. The recovery of increased TSPO levels was associated with the degree of remyelination and TSPO co-localized to microglia and astrocytes. We used small animal positron emission tomography (PET) to demonstrate that [11C]-( R)-PK11195 levels are significantly elevated in the living mouse brain during demyelination and normalized when remyelination is complete. TSPO-PET imaging provides a significant advance in monitoring brain injury and recovery in the same animal.; Finally, we used PET to investigate the in vivo dynamics of glial activation and dopamine synapses in a primate model of Parkinson's disease (PD). We found an early and selective loss of striatal vesicular monoamine transporter type-2 (VMAT-2) in asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animals. This effect was associated with increased glial activation and decreased in vivo dopamine release with no early effects on dopamine transporters (DAT) or D2 dopamine receptors. Striatal VMAT-2 and DAT decreased with the appearance of neurological dysfunction, but glial cell activation did not track disease progression. The present study suggests that the glial cell activation and the selective loss of VMAT-2 function are one of the earliest events in the pathophysiology of PD.; In summary, the present studies further support the notion that TSPO is a sensitive and selective marker for visualization and quantification of neuropathological changes in brain.