Free Radical Biology & Medicine 51 (2011) 1480–1481

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Free Radical Biology & Medicine

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Commentary

Ironing out neurodegeneration: Iron chelation for neuroprotection

Joshua L. DunaiefF.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA

E-mail address: jdunaief@upenn.edu.

0891-5849/$ – see front matter © 2011 Published by Edoi:10.1016/j.freeradbiomed.2011.05.009

The mechanism of neuroprotection by these iron chelators isprobably prevention of iron-catalyzed oxidative stress, as several of

a r t i c l e i n f o

Article history:

Received 5 May 2011Accepted 9 May 2011Available online 14 May 2011

the above studies correlate diminished oxidative stress with chelatoradministration. Iron excess, or mislocalization, has been associatedwith age-related neurodegeneration such as age-related maculardegeneration [7], Alzheimer disease [8], and Parkinson disease [9], soit is primed to exacerbate ongoing degeneration in these conditions. It

Iron is one of the substances for which the adage “Too much of agood thing is not better” holds true. Iron's ability to readily shift itsredox state facilitates cellular respiration but can also catalyze theproduction of harmful hydroxyl radical when iron's level or location isinappropriate. In this issue of Free Radical Biology & Medicine, thepaper by Obolensky et al. highlights the neuroprotective potential ofiron chelation, even when iron dysregulation is not the primary causeof the degeneration.

Their carefully executed study shows that retinal degeneration inrd10 mice can be ameliorated by treatment with the iron chelator zinc–deferoxamine (Zn-DFO). Rd10 mice have a mutation in the rodphotoreceptor phosphodiesterase, required for phototransduction,resulting in a nearly complete loss of both rod and cone photoreceptorsby about 6 weeks of age. Mice given Zn-DFO by ip injection beginning atpostnatal day4have relativelypreserved retinal structure and function atseveral ages, as well as diminished oxidative stress. The number of rodsand cones is higher in the treated mice. Electroretinography revealsimproved rod and cone function with the Zn-DFO treatment. Bothimmunostaining and biochemical assays reveal diminished oxidativestress in the Zn-DFO-treated mice.

This study builds upon several previous publications showingneuroprotection by iron chelation. DFO protects the rat retina fromphoto-oxidative stress [1] and from ischemia–reperfusion injury [2]. Theoral iron chelator deferiprone protects iron-overloaded retinas ofceruloplasmin/hephaestin knockout mice against oxidative stress andretinal degeneration. It also ameliorates a movement disorder and earlymortality associated with brain iron accumulation in these mice [3].Intraperitoneal injection of the endogenous iron-chelating proteintransferrin alsomarkedly protects the rd10 retina from degeneration [4].

Iron chelation can also protect the brain. The chelator salicylalde-hyde isonicotinoyl hydrazine protects the rodent spinal cord againsttrauma [5]. Both elevated levels of the endogenous iron-storageprotein ferritin and administration of the metal chelator clioquinolprotect the mouse brain against the neurotoxin MPTP, which inducesa Parkinson-like neurodegeneration [6].

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can also be released from red blood cells after hemorrhage, or fromdying neighbors in ongoing neurodegeneration.

Iron dysregulation caused by ongoing neurodegeneration couldalso accelerate disease. For example, retinas of rd10 mice have alteredlevels of iron, ferritin, and transferrin [10]. Iron may be mishandledduring neurodegeneration because its regulation is also influenced byinflammation and hypoxia, potentially leading to toxic iron stores.Inappropriate iron handling can clearly lead to brain and retinadegeneration, as in the hereditary diseases aceruloplasminemia [11],Friedreich ataxia [12], and pantothenate kinase-associated neurode-generation [13]. Mice with iron-regulatory protein knockout or lowferritin levels also experience neurodegeneration [14].

The above studies support the use of iron chelators in clinical trialsfor neurodegeneration such as in Alzheimer disease [15] and Friedreichataxia [16]. Route of administration and toxicity are importantconsiderations. Some chelators can readily cross the blood–brain andblood–retinal barriers. Iron deficiency must be avoided, but it is likelythat this could be achieved by careful monitoring and by choosingchelators that can bind or redistribute loosely bound, potentially toxiciron in the central nervous system without stripping iron from iron-requiring proteins.

References

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[2] Zhu, Y.; Zhang, L.; Gidday, J. M. Deferroxamine preconditioning promotes long-lasting retinal ischemic tolerance. J. Ocul. Pharmacol. Ther. 24:527–535; 2008.

[3] Hadziahmetovic, M., et al. The oral iron chelator deferiprone protects against ironoverload-induced retinal degeneration. Invest. Ophthalmol. Vis. Sci. 52:959–968;2011.

[4] Picard, E., et al. Overexpressed or intraperitoneally injected human transferrinprevents photoreceptor degeneration in rd10 mice.Mol. Vis. 16:2612–2625; 2010.

[5] Rathore, K. I., et al. Ceruloplasmin protects injured spinal cord from iron-mediatedoxidative damage. J. Neurosci. 28:12736–12747; 2008.

[6] Kaur, D., et al. Genetic or pharmacological iron chelation prevents MPTP-inducedneurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37:899–909; 2003.

[7] Hahn, P.; Milam, A. H.; Dunaief, J. L. Maculas affected by age-related maculardegeneration contain increased chelatable iron in the retinal pigment epitheliumand Bruch's membrane. Arch. Ophthalmol. 121:1099–1105; 2003.

[8] Smith, M. A., et al. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. U. S. A. 94:9866–9868; 1997.

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[9] Lv, Z., et al. Increased iron levels correlate with the selective nigral dopaminergicneuron degeneration in Parkinson's disease. J. Neural Transm. 118:361–369; 2011.

[10] Deleon, E., et al. Alteration in iron metabolism during retinal degeneration in rd10mouse. Invest. Ophthalmol. Vis. Sci. 50:1360–1365; 2009.

[11] Dunaief, J. L., et al. Macular degeneration in a patient with aceruloplasminemia, adisease associated with retinal iron overload. Ophthalmology 112:1062–1065; 2005.

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[13] Lee, J. H., et al. Nigropallidal iron accumulation in pantothenate kinase-associatedneurodegeneration demonstrated by susceptibility-weighted imaging. J. Neurol.257:661–662; 2010.

[14] Rouault, T. A. Iron on the brain. Nat. Genet. 28:299–300; 2001.[15] Cuajungco, M. P., et al. Metal chelation as a potential therapy for Alzheimer's

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