Central proinflammatory stimuli exacerbates neurodegeneration in a Parkinson ’ s Disease Model.

POTT GODOY M. C.; TARELLI, R.; FERRARI, C.; PITOSSI, F. J

Esposende, Portugal

Workshop; Novel Molecular strategies to treat Neurodegenerative diseases; 2007

FENS

Parkinson‘s Disease (PD) is a neurodegenerative disease of unclear etiology and ill-defined pathophysiology. Activated microglia in the substantia nigra (SN) is found in all animal models and PD patients. However, microglia can have detrimental and protective functions in PD. In this study, we tested the hypothesis that a sub-toxic dose of an inflammogen (lipopolysaccharide (LPS)) can shift microglia to a pro-inflammatory state and exacerbate disease progression in an animal model of PD. Central  LPS injection in a degenerating SN exacerbated neurodegeneration, accelerated and increased motor symptoms and shifted microglial activation towards a pro-inflammatory phenotype with increased IL-1b secretion. Glucocorticoid treatment and specific IL-1 inhibition reversed these effects. Importantly, a systemic, chronic expression of IL-1 also exacerbated neurodegeneration and microglial activation in the SN. In vitro, IL-1 could directly exacerbate 6-OHDA-triggered dopaminergic toxicity. In vivo, we found that nitric oxide could also be responsable for the exacerbation of neurodegeneration observed. Thus, we conclude that IL-1 is exerting its exacerbating effect on degenerating dopaminergic neurons by direct and indirect mechanisms..This work demonstrates an unequivocal association between IL-1 overproduction and increased disease progression, pointing to inflammation as a risk factor for PD and suggesting that inflammation should be efficiently handled in PD patients to diminish acceleration of disease progression.