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The Journal of Neuroscience, July 15, 2002, 22(14):5848-5855

The Relationship between Intracellular Free Iron and Cell Injury in Cultured Neurons, Astrocytes, and Oligodendrocytes

Geraldine J. Kress, Kirk E. Dineley, and Ian J. Reynolds

Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Iron is an essential element for cells but may also be an important cytotoxin. However, very little is known about iron transport, redox status, or toxicity specifically inside cells. In this study, we exploited the sensitivity of fura-2 to quenching by ferrous iron (Fe²⁺) to detect intracellular free iron ([Fe²⁺]_i) in neurons, astrocytes, and oligodendrocytes in primary culture. All cell types exposed to Fe²⁺ in the presence of the ionophore pyrithione rapidly accumulated Fe²⁺ to a similar extent. The heavy-metal chelators bipyridyl and N,N,N',N'-tetrakis(2-pyridalmethyl)ethyl-enediamine rapidly reversed the increase in [Fe²⁺]_i, whereas desferrioxamine had little effect. Interestingly, the Fe²⁺-mediated quenching of fura-2 fluorescence was reversed in a concentration-dependent manner by hydrogen peroxide. This was likely caused by the oxidation of Fe²⁺ to Fe³⁺ inside the cell. Acute exposure of cells to Fe²⁺ was only toxic when the metal was applied together with pyrithione, showing that Fe²⁺ is only toxic when elevated inside cells. Interestingly, only neurons and oligodendrocytes were injured by this elevation in [Fe²⁺]_i, whereas astrocytes were unaffected, although [Fe²⁺]_i was elevated to the same degree in each cell type. These studies provide a novel approach for detecting [Fe²⁺]_i in a manner sensitive to the redox state of the metal. These studies also provide a model system for the study of the toxic consequences of elevated [Fe²⁺]_i in neural cells.

Key words: intracellular iron; fura-2; fluorescent dye; neuron; astrocyte; oligodendrocyte

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22145848-08$05.00/0

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