Iron protects astrocytes from 6-hydroxydopamine toxicity.
The role of iron in 6-hydroxydopamine (6-OHDA) toxicity towards astrocytes was investigated in vitro using rat primary astrocytes, rat astrocytoma cell line C6, and human astrocytoma cell line U251. The assessment of mitochondrial respiration or lactate dehydrogenase release has shown a dose-dependent decrease in the viability of astrocytes treated with 6-OHDA, which coincided with DNA fragmentation and the changes in cellular morphology. This was a consequence of the oxidative stress mediated by 6-OHDA autoxidation products hydrogen peroxide, superoxide anion, and hydroxyl radical. Both FeSO(4) and FeCl(3) markedly alleviated detrimental effects of 6-OHDA treatment, while MgSO(4) was without effect. The protective action of iron was neutralized by a membrane-permeable iron chelator o-phenanthroline, which also augmented astrocyte killing in the absence of exogenous iron. The mechanisms responsible for iron-mediated protection of astrocytes did not involve interference with either 6-OHDA autoxidation, hydrogen peroxide toxicity, or 6-OHDA-induced activation of extracellular signal-regulated kinase. Finally, the addition of iron potentiated and its chelation blocked 6-OHDA toxicity towards neuronal PC12 cells, suggesting the opposite roles for this transition metal in regulating the survival of astrocytes and dopaminergic neurons.
Raicevic
Nevena
N
Department of Neurobiology and Immunology, Institute for Biological Research, Belgrade, Serbia and Montenegro.
Mladenovic
Aleksandra
A
Perovic
Milka
M
Harhaji
Ljubica
L
Miljkovic
Djordje
D
Trajkovic
Vladimir
V
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005290:Ferric Compounds / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D006892:Hydroxydopamines / Q000633:toxicity*; D007501:Iron / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D062726:Junctional Adhesion Molecules; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010618:Phenanthrolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling / Q000379:methods; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
D015815:Cell Adhesion Molecules; D005290:Ferric Compounds; D006892:Hydroxydopamines; D007502:Iron Chelating Agents; D062726:Junctional Adhesion Molecules; D010618:Phenanthrolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D007501:Iron; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; C025205:1,10-phenanthroline