RT Journal Article
SR Electronic
T1 A new mouse model of prostaglandin J2 (PGJ2) induced neuroinflammation and parkinsonism: Validation using μPET and C-11 labeled radiotracers
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1810
OP 1810
VO 55
IS supplement 1
A1 Anastasia Nikolopoulou
A1 Kai-Yvonne Shivers
A1 Paresh Kothari
A1 Bin He
A1 Maria Figueiredo-Pereira
A1 Paul Mozley
A1 Shankar Vallabhajosula
YR 2014
UL http://jnm.snmjournals.org/content/55/supplement_1/1810.abstract
AB 1810 Objectives Neuroinflammation (NI) has been implicated in Parkinson’s disease (PD). Drug therapies through NI modulation hold a great promise. PGJ2, an endogenous neurotoxic metabolite of arachidonic acid (AA), up-regulates cyclooxygenase-2 potentially causing a positive feedback loop that could lead to chronic NI. This study was designed to validate this new mouse model using inflammation and dopaminergic specific radiotracers. [11C](R)PK11195 (PK) binds specifically to translocator protein (TSPO) in activated microglia, [11C]AA metabolism is increased in NI. [11C]PE2i (PE2i) binds to presynaptic dopamine transporters (DAT) and [11C]Raclopride (RAC) binds to postsynaptic DA D2 receptors. Methods Adult male FVB mice underwent 4 unilateral microinjections of PGJ2 (16.7µg) or vehicle (DMSO) into the right (R) substantia nigra (SN) at 1-wk intervals. The intact left (L) contralateral side served as control. µPET studies were performed between 1-14 wks after last PGJ2 treatment. The ratio of activity in the PGJ2 or DMSO treated side to control side (R/L) was estimated. Results Over a period of 1-9 wks, PK scans showed microglia activation linked to PGJ2 treatment compared to DMSO (1.90±0.26 vs 1.09±0.37 at 9 wks). Upregulation of AA metabolism was also evident in PGJ2-treated mice (1.31±0.25 vs 0.84±0.10 at 9 wks). Over a period of 7-14 wks, the uptake of PE2i in PGJ2-treated mice decreased significantly in a pattern consistent with loss of presynaptic DAT on axons originating in the SN (0.16±0.05 vs 0.53±0.09 at 14 wks). In contrast, Rac-PET showed that PGJ2 did not trigger any changes in DA D2 receptors (1.04±0.28 vs 0.93±0.04 at 8 wks). Conclusions The μPET imaging studies clearly validate the new mouse model of PGJ2 induced NI and PD. These results clearly demonstrate the potential significance of the PGJ2 induced NI mouse model in PD research and the evaluation of anti-inflammation therapies.