Fig. 9.

Scheme depicting novel and previously tested therapeutic agents (in green) that could have potential to treat PD. (1) DP2 receptor antagonists: in the SNpc, DP2 receptors were detected in dopaminergic neurons but not in microglia. DP2 receptor activation leads to a decrease in cAMP and an increase in calcium. These effects mediate neurotoxicity induced by DP2 receptor activation. Thus, DP2 receptor antagonists could potentially prevent DA neurodegeneration. (2) COX-inhibitors: Ibuprofen, a COX inhibitor, prevented many of the sequelae induced by the PGJ2 treatment. Our data support the epidemiological studies that report the beneficial effect of NSAIDs in lowering the risk of developing PD. (3) L-PGDS inhibitors: in the brain, this enzyme synthesizes PGD2 from PGH2. PGD2 and its metabolite PGJ2 can be neurotoxic. Thus, decreasing L-PGDS activity will lower PGD2 levels and could prevent or diminish the neurotoxic effects of PGD2/J2 on dopaminergic neurons. COX 1 and 2, cyclooxygenase 1 and 2; L-PGDS, lipocalin prostaglandin D synthase; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; PPARγ, peroxisome proliferator-activated receptor gamma; PET, positron emission tomography (see text for details)