AIMS :The major goal of this project was to examine the roles of glial cells in iflammation-related neurodegeneration. We have employed both in vitro and in vivo rodent models of Parkinson's disease by focusing our studies on the mesencephalic dopaminergic neurons. Our laboratory was among the first to report that lipopolysaccharide (LPS)-induced neurotoxicity depended on the presence of glial cells. These cells secrete a variety of proinflammatory factors, including cytokines, free radicals and arachidonate metabolites that are the main contributors to the pathogenesis of inflammation-related neurodegenerative diseases. Our current efforts focus on determining the relative importance of these proinflammatory factors in glia-mediated neuronal damage. ACCOMPLISHMENTS :The etiology and underlying mechanism of action for the selective and progressive loss of dopaminergic neurons in the substantia nigra for idiopathic Parkinson's disease remain poorly understood. Increasing evidence has suggested a role for inflammation and oxidative stress in the brain in the pathogenesis of this neurological disorder. We report here that chronic intranigral infusion into the rat brain of lipopolysaccharide (LPS) at 5 ng/hr for two weeks induced a rapid activation of microglia, the brain immune cells, followed by a time-dependent and selective degeneration of nigral dopaminergic neurons. At 12 weeks after the initiation of LPS infusion, 80% of the nigral dopaminergic neurons were destroyed. Consistent with in vivo observation, treatment of rat mesencephalic mixed neuron-glia cultures with 0.1-10 ng/ml for up to 10 days resulted in a dose- and time-dependent and selective degeneration of dopaminergic neurons which was preceded by the activation of microglia and production of neurotoxic factors. Furthermore, a distinct pattern for the production of neurotoxic factors was observed for activated microglia. Significant production of nitric oxide, tumor necrosis factor a, and superoxide was detected in cultures treated with 1-10 ng/ml LPS and inhibition of nitric oxide production as well as neutralization of the reactivity of superoxide afforded partial yet significant neuroprotection. In contrast, in cultures treated with 0.1-0.3 ng/ml LPS, only the production of superoxide was observed and a near complete neuroprotection was observed with antioxidants only. These results indicate that chronic exposure to an inflammagen was sufficient to induce selective degeneration of dopaminergic neurons in the rat substanitia nigra and that microglia-originated reactive oxidative species play a major role in inflammation-mediated selective degeneration of dopaminergic neurons in the rat model of Parkinson's disease.
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