Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease.
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-1beta (IL-1beta) 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.
Pott Godoy
María Clara
MC
Fundación Instituto Leloir, FBMC-UBA, CONICET, Patricias Argentinas 435, (1405) Buenos Aires, Argentina.
Tarelli
Rodolfo
R
Ferrari
Carina Cintia
CC
Sarchi
Maria Inés
MI
Pitossi
Fernando Juan
FJ
D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005938:Glucocorticoids / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D011597:Psychomotor Performance; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology
D005938:Glucocorticoids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D003907:Dexamethasone; D016627:Oxidopamine