Program Project on the Pathogenesis and Treatment of Parkinson's Disease

MPTP (l-methyl-4-phenyl-,2, 3, 6-tetrahydropyridine is the tool of choice for investigations into the cascade of events that lead to arkinson's Disease (PD). Herein, we investigated the role of inflammation in PD using the MPTP mouse model of PD. We found that APTP causes a robust microglial activation which is accompanied by the up-regulation of inducible nitric oxide synthase (iNOS) and fcell surface markers such as macrophage activating complex-I (MAC-i) as well as the production of cytotoxic molecules such as eactive oxygen species (ROS) nitric oxide (NO) and a host of proinflammatory cytokines like interleukin-1$, cyclooxygenase-2 and he prostaglandin PG%. We also noted that NADPH oxidase, a multimeric enzyme that is a major source of the superoxide radical, is p-regulated in ventral midbrains of MPTh-treated mice and in tissues from PD brains. Although both the COX-2 enzyme and PGE2 ere also up-regulated in MPTP-treated mouse ventral midbrains, only COX-2 was up-regulated in PD brains. Minocycline, a etracycline antibiotic that has anti-inflammatory action independent of its antimicrobial action, attenuated most of the microglial- elated events caused by MPTP. Thus, inflammation may push the progressive nature of PD through microglial activation and may be ideal point for therapeutic intervention in PD.