NOVEL ANTI-INFLAMMATORY THERAPIES FOR PD

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. We 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, we now propose to examine neuroprotection of the dopaminergic system by anti-inflammatory agents. Based on several studies, we hypothesize that a cyclooxygenase (COX) 1 and 2 inhibitor (indomethecin [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 nigro-striatal dopaminergic system follows repeated MPTP treatment. Using PET scanning with a receptor ligand for the peripheral benzodiazepine receptor site (11C-PK11195), our preliminary experiments indicate that we can visualize the neuroinflammatory reactions during CNS DA degeneration (as determined by 11C-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.