Activation of microglia by human neuromelanin is NF-kappaB dependent and involves p38 mitogen-activated protein kinase: implications for Parkinson's disease.
It has been suggested that microglial inflammation augments the progression of Parkinson's disease (PD). However, endogenous factors initiating microglial activation are largely unknown. We therefore investigated the effects of human neuromelanin (NM) on the release of neurotoxic mediators and the underlying signaling pathways from rat microglia in vitro. The addition of NM to microglial cultures induced positive chemotactic effects, activated the proinflammatory transcription factor nuclear factor kappaB (NF-kappaB) via phosphorylation and degradation of the inhibitor protein kappaB (IkappaB), and led to an up-regulation of tumor necrosis factor alpha, interleukin-6, and nitric oxide. The impairment of NF-kappaB function by the IkappaB kinase inhibitor sulfasalazine was paralleled by a decline in neurotoxic mediators. NM also activated p38 mitogen-activated protein kinase (MAPK), the inhibition of this pathway by SB203580 diminished phosphorylation of the transactivation domain of the p65 subunit of NF-kappaB. These findings demonstrate a crucial role of NM in the pathogenesis of PD by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin, and chronification of inflammation. The antagonization of microglial activation by a pharmacological intervention targeting microglial NF-kappaB or p38 MAPK could point to additional venues in the treatment of PD.
Wilms
Henrik
H
Klinik für Neurologie, Christian-Albrechts-Universität zu Kiel, 24105 Kiel, Germany. h.wilms@neurologie.uni-kiel.de
Rosenstiel
Philip
P
Sievers
Jobst
J
Deuschl
Günther
G
Zecca
Luigi
L
Lucius
Ralph
R
D000818:Animals; D002478:Cells, Cultured; D002633:Chemotaxis; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000209:etiology; D018836:Inflammation Mediators / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008543:Melanins / Q000494:pharmacology*; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D010300:Parkinson Disease / Q000276:immunology; D010766:Phosphorylation; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases
D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008543:Melanins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; C014121:neuromelanin; D000072000:NF-KappaB Inhibitor alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases