title: Human neuromelanin: an endogenous microglial activator for dopaminergic neuron death.
abstract: Substantial evidence indicates that neuroinflammation caused by microglial activation in substantia nigra is critical in the pathogenesis of dopaminergic neurodegeneration in Parkinson's disease (PD). Increasing data demonstrates that environmental factors such as rotenone, paraquat play pivotal roles in dopaminergic neuron death. Here, potential role and mechanism of neuromelanin (NM), a major endogenous component in dopaminergic neurons of substantia nigra, on microglial activation and associated dopaminergic neurotoxicity were investigated. Using multiple primary mesencephalic cultures, we found that HNM caused dopaminergic neurodegeneration characterized by the decreased dopamine uptake and reduced numbers and shorted dendrites. HNM was selectively toxic to dopaminergic neurons since the other types of neurons determined by either gamma-aminobutyric acid uptake and total neuronal numbers showed smaller decrease. HNM produced modest dopaminergic neurotoxicity in neuron-enriched cultures; in contrast, much greater neurotoxicity was observed in the presence of microglia. HNM morphologically activated microglia and produced proinflammatory and neurotoxic factors. Thus, HNM can be a potent endogenous activator of microglial reactivation, mediating PD progression. Hence, inhibition of microglial reactivation can be a useful strategy for PD therapy.
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, PR China. ttyyzw@yahoo.com.cn
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Luigi
authors.initials: L
authors.lastname: Zecca
authors.forename: Belinda
authors.initials: B
authors.lastname: Wilson
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Ren
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Wang
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Wang
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008543:Melanins / Q000378:metabolism* / Q000494:pharmacology; D017628:Microglia / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008543:Melanins; D014409:Tumor Necrosis Factor-alpha; C014121:neuromelanin; D009569:Nitric Oxide; D004298:Dopamine