title: Iron inhibits neurotoxicity induced by trace copper and biological reductants.
abstract: The extracellular microenvironment of the brain contains numerous biological redox agents, including ascorbate, glutathione, cysteine and homocysteine. During ischemia/reperfusion, aging or neurological disease, extracellular levels of reductants can increase dramatically owing to dysregulated homeostasis. The extracellular concentrations of transition metals such as copper and iron are also substantially elevated during aging and in some neurodegenerative disorders. Increases in the extracellular redox capacity can potentially generate neurotoxic free radicals from reduction of Cu(II) or Fe(III), resulting in neuronal cell death. To investigate this in vitro, the effects of extracellular reductants (ascorbate, glutathione, cysteine, homocysteine or methionine) on primary cortical neurons was examined. All redox agents except methionine induced widespread neuronal oxidative stress and subsequent cell death at concentrations occurring in normal conditions or during neurological insults. This neurotoxicity was totally dependent on trace Cu (>or=0.4 microM) already present in the culture medium and did not require addition of exogenous Cu. Toxicity involved generation of Cu(I) and H(2)O(2), while other trace metals did not induce toxicity. Surprisingly, administration of Fe(II) or Fe(III) (>or=2.5 microM) completely abrogated reductant-mediated neurotoxicity. The potent protective activity of Fe correlated with Fe inhibiting reductant-mediated Cu(I) and H(2)O(2) generation in cell-free assays and reduced cellular Cu uptake by neurons. This demonstrates a novel role for Fe in blocking Cu-mediated neurotoxicity in a high reducing environment. A possible pathogenic consequence for these phenomena was demonstrated by abrogation of Fe neuroprotection after pre-exposure of cultures to the Alzheimer's amyloid beta peptide (Abeta). The loss of Fe neuroprotection against reductant toxicity was greater after treatment with human Abeta1-42 than with human Abeta1-40 or rodent Abeta1-42, consistent with the central role of Abeta1-42 in Alzheimer's disease. These findings have important implications for trace biometal interactions and free radical-mediated damage during neurodegenerative illnesses such as Alzheimer's disease and old-age dementia.
authors.affiliation: Department of Pathology and Centre for Neuroscience, The University of Melbourne, 3010, Carlton South, Victoria, Australia. arwhite@unimelb-edu.au
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Xudong
authors.initials: X
authors.lastname: Huang
authors.forename: Irene
authors.initials: I
authors.lastname: Voltakis
authors.forename: Konrad
authors.initials: K
authors.lastname: Beyreuther
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D003300:Copper / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007501:Iron / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects; D014131:Trace Elements / Q000037:antagonists & inhibitors / Q000633:toxicity
chemical_list: D014131:Trace Elements; D003300:Copper; D007501:Iron