Tracking PGJ2-induced inflammation in rat brain using µPET and TSPO ligand [11C](R)PK11195

Objectives -

Methods Adult male Sprague-Dawley rats (18-20 wks of age) were divided in two groups with five rats per group. Rats received two unilateral injections (one per week) of 2 uL PGJ2 (33.4 ug in 17% DMSO in PBS) or vehicle (17% DMSO in PBS) into the right SN. The intact contralateral side served as the basal level for each rat. Dynamic 60-min µPET was performed following administration of [¹¹C](R)PK11195 (37-74 MBq) via tail vein at week 4 and 8 after the last PGJ2 injection. Total volumes of distribution (V_T) of the radiotracer were calculated by Logan plot with image-derived input function using the vena cava as a region of interest (ROI). Validation of TSPO expression was performed by immunohistochemistry of brain tissues sections at the end of µPET study.

Results After intravenous injection of [¹¹C](R)PK11195, the lesioned side of rat brains showed significantly higher radioactivity uptake than the contralateral side. Logan plot analysis revealed that V_T ratio between the two sides was significantly higher in PGJ2-treated brains than in controls suggesting a PGJ2-related elevation of TSPO binding. At week 4 post last PGJ2 injection, the average of V_T ratio for PGJ2 rats was 1.56 ± 0.10 and for DMSO rats 1.23 ± 0.16 (P<0.01; unpaired t-test). At week 8 post last PGJ2 injection, distribution of [¹¹C](R)PK11195 uptake was similar to week 4 (PGJ2>DMSO), however, V_T ratios for both animal groups were found 17% decreased compared to the respective groups at week 4 (P<0.002; paired t-test).

Conclusions Our data demonstrate that two unilateral nigral injections of PGJ2 produce a robust increase in microglia activation in rat brains that is readily detected with PK-µPET. The PGJ2 rat model of NI mimics PD behavior and can be very useful to screening newly developed radiotracers and testing/following up the benefits of anti-inflammatory therapies by non-invasive imaging. Research Support: Supported by NIH [CTSC GRANT UL1-RR024996 (pilot award to JB & MEFP); GM060665 (RISE Training Program at Hunter College from NIGMS to MNS)] and by NSF 0965983 (IGERT Training Program at Hunter College to CC).