Detection of cytotoxic activation of microglia in a rat neuroinflammation model using a novel translocator protein ligand, [18F]FEPPA

Objectives Activated microglia are known to increase the expression of translocator protein (18 kDa) (TSPO). We evaluated whether a novel TSPO ligand, [18F]FEPPA could detect microglia in the cytotoxic state for acute reaction in rat neuroinflammation model.

Methods Nineteen rats (10 LPS, 9 vehicle) had 6-OHDA injected into the right striatum (ST). On day 4, 1st PET scans were performed for 60 min with an animal PET/CT scanner after an injection of [18F]FEPPA. Then lipopolysaccharide(LPS) for acute reaction or vehicle were administered intraperitoneally. After 4 hrs, PET scans were repeated. Rats were then euthanized and immunohistochemical staining and RT-PCR for inflammatory cytokines (TNFα, IL-1β) were performed for confirmation of the microglial activation and cytotoxic damage. Regions of interest were placed over the ST bilaterally on [18F]FEPPA PET images. Right/left (R/L) ST uptake ratios (30-60min) were compared between LPS and vehicle groups (gps).

Results In 1st PET scans, the R/L ST ratios in LPS gp (1.17 ± 0.15) were not significantly different from vehicle gp (1.12 ± 0.10)(p=0.37). However, in Repeated PET scans, the R/L ST ratios in LPS gp (1.31 ± 0.26) were significantly higher than in vehicle gp (1.09 ± 0.14)(p=0.04). Percent increase of the R/L ST ratios in each gp between 1st and repeated PET scans were significantly higher in LPS gp (11.6 ± 12.0) than in vehicle gp (-1.5 ± 14.1)(p=0.04). Activated microglia was exclusively observed on R ST in both LPS and vehicle gps histochemically. LPS gp showed higher expression of inflammatory cytokines than in vehicle gp indicating cytotoxic activation was induced by LPS treatment.

Conclusions These results suggest that TSPO binding as measured by [18F]FEPPA PET appears a promising for detection of cytotoxic activation of microglia in a rat neuroinflammation model