title: Loss of dopaminergic neurons by the induction of inducible nitric oxide synthase and cyclooxygenase-2 via CD 40: relevance to Parkinson's disease.
abstract: A glial reaction associated with up-regulation of inflammatory molecules has been suggested to play an important role in dopaminergic neuron loss in Parkinson's disease (PD). Among inflammatory molecules, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been focused upon as key factors in the pathogenesis. However, the mechanism of how these molecules are induced in PD brains is not clearly understood. We focused on CD 40, which is expressed on neural cells and could be implicated in the neuroinflammation by inducing inflammatory molecules. We showed that both iNOS and COX-2 were up-regulated in microglia and astrocytes by CD 40 stimulation in association with a low dose of interferon-gamma (IFN-gamma) in vitro. Selective loss of dopaminergic neurons was induced by costimulation with CD 40 and IFN-gamma in mesencephalic cultures, which was protected by selective inhibitors of iNOS and/or COX-2. We also found in CD 40-stimulated astrocytes an increase of a low-affinity IgE receptor CD 23, which is known to induce iNOS expression. Together these data suggest that up-regulated iNOS and COX-2 via the CD 40 pathway may lead to dopaminergic neuron loss and may participate in the neuroinflammaory pathway of PD.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakatsuji
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Moriya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Hisae
authors.initials: H
authors.lastname: Sumi
authors.forename: Harutoshi
authors.initials: H
authors.lastname: Fujimura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019013:CD40 Antigens / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004298:Dopamine / Q000502:physiology*; D004790:Enzyme Induction / Q000502:physiology; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D008636:Mesencephalon / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology*; D017455:Receptors, IgE / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019013:CD40 Antigens; D017455:Receptors, IgE; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D004298:Dopamine