Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [(11)C]PK11195 in rats

Abstract

Objective: The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [(11)C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [(11)C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation.

Methods: On day 1, a small aliquot of absolute ethanol was injected into the rat right striatum (ST) to produce artificial brain injury. On day 3, MRI scans were performed to evaluate and select rats showing a similar degree of brain injury. Then LPS or vehicle was administered intraperitoneally. On day 4, PET scans were performed after a bolus injection of [(11)C]PK11195. Eleven rats (7 LPS administered rats, 4 LPS non-administered rats) were evaluated. We used uptake ratios of the integral of right and left striatum from 0 to 60 min as an estimate of PBR distribution volume (V (60)). The number of activated microglia and mRNA expression of inflammatory cytokines (TNFalpha, IL-1beta) were assessed by isolectin-B4 staining and RT-PCR, respectively.

Results: Right/left ST V (60) ratios of LPS group were significantly higher than those of non-LPS group (P < 0.03). Although there were no significant differences in the number of activated microglia between the two groups, LPS group showed higher expression of inflammatory cytokines (TNFalpha, IL-1beta) than the non-treated group indicating that further activation was induced by LPS treatment.

Conclusion: The results suggest that intensity of PBR signals in [(11)C]PK11195 PET may be related to the level of microglial activation rather than the number in activated microglia at least in an artificial brain injury model.