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 Posted: Mon Nov 24, 2008 3:02 am Post subject: Toxic Iron From Healthy Iron |
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"Dysregulation of localized iron homeostasis"
Iron prochelator BSIH protects retinal pigment epithelial cells
against cell death induced by hydrogen peroxide
Louise K. Charkoudiana, Tzvete Dentchevb, Nina Lukinovab, Natalie
Wolkowb, Joshua L. Dunaiefb and Katherine J. Franza, ,
aDepartment of Chemistry, Duke University, Durham, NC 27708-0346,
United States
bF. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute,
University of Pennsylvania, Philadelphia, PA 19104, United States
Received 29 May 2008; revised 4 August 2008; accepted 13 August
2008. Available online 24 August 2008.
Abstract
Dysregulation of localized iron homeostasis is implicated in several
degenerative diseases, including Parkinson’s, Alzheimer’s, and age-
related macular degeneration, wherein iron-mediated oxidative stress
is hypothesized to contribute to cell death.
Inhibiting toxic iron without altering normal metal-dependent
processes presents significant challenges for standard small molecule
chelating agents.
We previously introduced BSIH (isonicotinic acid [2-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide)
prochelators that are converted by hydrogen peroxide into SIH
(salicylaldehyde isonicotinoyl hydrazone) chelating agents that
inhibit iron-catalyzed hydroxyl radical generation.
Here, we show that BSIH protects a cultured cell model for retinal
pigment epithelium against cell death induced by hydrogen peroxide.
BSIH is more stable than SIH in cell culture medium and is more
protective during long-term experiments.
Repetitive exposure of cells to BSIH is nontoxic, whereas SIH and
desferrioxamine induce cell death after repeated exposure.
Combined, our results indicate that cell protection by BSIH involves
iron sequestration that occurs only when the cells are stressed by
hydrogen peroxide.
These findings suggest that prochelators discriminate toxic iron from
healthy iron and are promising candidates for neuro- and retinal
protection.
Keywords: Iron; Oxidative stress; Reactive oxygen species; Fenton
chemistry; Chelation therapy
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