title: Manganese inhibits the ability of astrocytes to promote neuronal differentiation.
abstract: Manganese (Mn) is a known neurotoxicant and developmental neurotoxicant. As Mn has been shown to accumulate in astrocytes, we sought to investigate whether Mn would alter astrocyte-neuronal interactions, specifically the ability of astrocytes to promote differentiation of neurons. We found that exposure of rat cortical astrocytes to Mn (50-500 microM) impaired their ability to promote axonal and neurite outgrowth in hippocampal neurons. This effect of Mn appeared to be mediated by oxidative stress, as it was reversed by antioxidants (melatonin and PBN) and by increasing glutathione levels, while it was potentiated by glutathione depletion in astrocytes. As the extracellular matrix protein fibronectin plays an important role in astrocyte-mediated neuronal neurite outgrowth, we also investigated the effect of Mn on fibronectin. Mn caused a concentration-dependent decrease of fibronectin protein and mRNA in astrocytes lysate and of fibronectin protein in astrocyte medium; these effects were also antagonized by antioxidants. Exposure of astrocytes to two oxidants, H2O2 and DMNQ, similarly impaired their neuritogenic action, and led to a decreased expression of fibronectin. Mn had no inhibitory effect on neurite outgrowth when applied directly onto hippocampal neurons, where it actually caused a small increase in neuritogenesis. These results indicate that Mn, by targeting astrocytes, affects their ability to promote neuronal differentiation by a mechanism which is likely to involve oxidative stress.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Giordano
authors.forename: Daniella
authors.initials: D
authors.lastname: Pizzurro
authors.forename: Kathryn
authors.initials: K
authors.lastname: VanDeMark
authors.forename: Marina
authors.initials: M
authors.lastname: Guizzetti
authors.forename: Lucio G
authors.initials: LG
authors.lastname: Costa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000187:drug effects / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002712:Chlorides / Q000633:toxicity*; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D017895:Manganese Compounds; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
chemical_list: D000975:Antioxidants; D002712:Chlorides; D005353:Fibronectins; D017895:Manganese Compounds; D016877:Oxidants; D012333:RNA, Messenger; D005978:Glutathione; C025340:manganese chloride