A recent large Parkinson's Disease (PD) twin study indicates that environmental and toxic factors play major roles in causing typical PD (Tanner, et. al. JAMA, 1999). Interestingly, neuroinflammation seen in the caudate-putamen is a part of the pathophysiology (Brooks, 1999). The progressive decline of dopamine (DA) terminals seen in idiopathic PD can be closely modeled in Macaca fascicularis by low-dose exposure to the mitochondrial toxin, MPTP, over nine to fourteen months. The investigators demonstrated by PET imaging of DA terminal and MRS that such primates provide a physiological chart of degeneration and appearance of PD signs (Brownell, et. al., Nat. Med., 1998). This data profile enables the design of an experimental paradigm for realistically determining toxicity, neuroinflammation and neuroprotection in idiopathic PD. In this project using the PD primate model, the investigators now propose to examine neuroprotection of the dopaminergic system by anti-inflammatory agents. Based on several studies, they hypothesize that a cyclooxygenase (COX) 1 and 2 inhibitor (indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-H-indole-3-acetic acid]) can decrease inflammatory reactions caused by MPP+ toxicity and also reduce chronic neurodegenerative processes. In the non-human primate, a slow progressive lesion of the nigrostriatal dopaminergic system follows repeated MPTP treatment. Using PET scanning with a receptor ligand for the peripheral benzodiazepine receptor site (11-C-PK1 1195), preliminary experiments indicate that they can visualize the neuroinflammatory reactions during CNS DA degeneration (as determined by 11-C-CFT). These measurements will be combined with MRI and MRS studies of lactate and choline as in vivo biomarkers for the glial inflammatory and toxic responses of the nigrostriatal system. As a therapy, during and after neurotoxic exposure to MPTP, the investigators will treat the PD primates with a COX I and 2 inhibitor to evaluate anti- inflammatory prevention of onset and continued degeneration. Protection of the dopaminergic system by anti-inflammatory agents would be of tremendous therapeutic value for PD.
