Brain Advance Access published online on May 26, 2008
Brain, doi:10.1093/brain/awn101
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Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease
1Fundación Instituto Leloir, FBMC-UBA, CONICET, Patricias Argentinas 435. (1405) and 2Cátedra de Matemáticas – Facultad de Farmacia y Bioquímica, Junín 954, Buenos Aires, Argentina
Correspondence to:
Fernando Pitossi, Fundación Instituto Leloir, FBMC-UBA, CONICET, Patricias Argentinas 435, (1405) Buenos Aires, Argentina E-mail: fpitossi{at}leloir.org.ar
Parkinson's disease is a neurodegenerative disorder with uncertain aetiology and ill-defined pathophysiology. Activated microglial cells in the substantia nigra (SN) are found in all animal models of Parkinson's disease and patients with the illness. Microglia may, however, have detrimental and protective functions in this disease. In this study, we tested the hypothesis that a sub-toxic dose of an inflammogen (lipopolysaccharide) can shift microglia to a pro-inflammatory state and exacerbate disease progression in an animal model of Parkinson's disease. Central lipopolysaccharide injection in a degenerating SN exacerbated neurodegeneration, accelerated and increased motor signs and shifted microglial activation towards a pro-inflammatory phenotype with increased interleukin-1β (IL-1β) secretion. Glucocorticoid treatment and specific IL-1 inhibition reversed these effects. Importantly, chronic systemic expression of IL-1 also exacerbated neurodegeneration and microglial activation in the SN. In vitro, IL-1 directly exacerbated 6-OHDA-triggered dopaminergic toxicity. In vivo, we found that nitric oxide was a downstream molecule of IL-1 action and partially responsible for the exacerbation of neurodegeneration observed. Thus, IL-1 exerts 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 Parkinson's disease and suggesting that inflammation should be efficiently handled in patients to slow disease progression.
Key Words: Parkinson's disease; inflammation; neurodegeneration; IL-1; LPS
Abbreviations: Ad, adenoviral vector; β-gal, beta-galactosidase; DXM, dexamethasone; GSA, Griffonia Simplicifolia Lectin I Isolectin B4; IL-1, interleukin 1; IL-1ra, IL-1 receptor antagonist; rIL-1 β, rat Interleukin 1 beta; i.v., intravenous; LPS, lipopolysaccharide; MHC, major histocompatibility complex; SMT, S-methylisothiourea; TH, tyrosine hydroxylase; Veh, vehicle
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Received November 9, 2007. Revised April 21, 2008. Accepted May 1, 2008.
*These authors contributed equally to this work
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