Given that age-related macular degeneration may be caused by iron- mediated oxidative damage, it is reasonable to assume that antioxidants and iron chelators may be effective in reducing the occurrence and progression of AMD. While the Age-Related Eye Disease Study has shown that supplemental zinc, vitamin C, vitamin E, and β-carotene can provide a protective effect on AMD progression, it is likely that additional antioxidants may further prevent or slow the progression of AMD. Since iron is one of the most potent generators of oxidative damage through production of hydroxyl radicals in the Fenton reaction, and since the antioxidants used in the AREDS study may not quench all of the hydroxyl radical produced by iron, it is possible that iron chelators will prove a useful adjunct to AREDS vitamins. Several reports suggest that iron chelation may play a role in the treatment of a number of neurological diseases such as Alzheimer’s disease and Parkinson’s disease, Huntington’s disease and Friedreich’s Ataxia (Zheng et al., 2005
; Richardson, 2004
). It is plausible that iron chelation may also be useful in retinal disease associated with iron overload.
However, there are many challenges with using clinically-available iron chelators to prevent and treat retinal degeneration. Ideally, an iron chelator should selectively bind iron and not other biologically important divalent metals such as Zn2+
(Liu and Hider, 2002
). In addition, an effective iron chelator must reach its target sites at a sufficiently high level; the chelator must be able to be absorbed in sufficient quantity through the gastrointestinal tract, the blood-brain barrier (BBB), or in the case of the retina, the blood-retina barrier. In order to successfully penetrate the blood-brain/blood-retinal barrier, an iron chelator must possess appreciable lipid solubility (Kalinowski and Richardson, 2005
) and small molecular size, ideally below 500 Daltons (Maxton et al., 1986
). An ideal iron chelator should additionally be uncharged in order to cross the BBB effectively (Richardson et al., 1990
; Aouad et al., 2002
Until recently the only iron chelator in widespread clinical use in the United States was deferoxamine B (DFO), and despite being a relatively effective iron chelator for the treatment of transfusional iron overload, it has many notable limitations. The drug is an inefficient iron chelator; typically only 5% or less of the drug administered promotes iron excretion (Bergeron et al., 2002
). In addition, because the drug is poorly absorbed by the gastrointestinal system, and its elimination from the body is rapid, effective DFO treatment requires subcutaneous (SC) or IV administration for 9 to 12 hours for 5 or 6 days each week (Lee et al., 1993
; Pippard, 1989
). Therefore, for patients requiring chronic treatment, chelation with DFO is costly, inefficient, cumbersome, and unpleasant. Perhaps more significantly, there can be some rare but potentially serious side effects associated with DFO administration, including pulmonary toxicity, bony changes, growth failure, and promotion of Yersinia enterocolitica
infections (Tenenbein et al., 1992
; Brill et al., 1991
; De Virgiliis et al., 1988
DFO treatment can also sometimes result in retinotoxicity, making it a dubious candidate for the treatment of AMD or other ocular diseases (Olivieri et al., 1986
). Haimovici et al
., describe macular and peripheral pigmentary changes, as well as reduction in retinal function as evidenced by decreases in ERG amplitude and EOG light-peak to dark-trough ratios (Haimovici et al., 2002
). Patients who are treated with DFO should thus be followed closely with routine ophthalmologic consultation; FA, ERG and EOG testing may be more helpful in identifying early and more widespread retinal injury than fundus examination alone.
More recently, several other iron chelators have been put into clinical use, including deferiprone (L1) and deferasirox (Exjade). Deferiprone has the advantage of being orally active and has been shown to be a more efficient iron chelator than DFO in removing cardiac iron, the cause of most of the mortality in transfusional iron overload (Anderson et al., 2002
). A recent report demonstrates the ability of L1 to decrease brain iron in patients with Friedreich’s Ataxia (Boddaert et al., 2007
). This result suggests that L1 may similarly decrease retinal iron levels. Development of rare but serious side-effects of L1 may be avoided by careful monitoring. These include hepatic fibrosis, agranulocytosis, neutropenia, and arthropathy (Olivieri et al., 1986
; Cohen et al., 2003
; Ceci et al., 2002
). The cause of deferiprone-related side effects is not currently known, but it may be due to the fact that deferiprone is a bidentate iron chelator. At low concentrations, bidentate iron chelators can actually facilitate the formation of free-radicals from the formation of incomplete iron chelator:iron 1:1 and 2:1 complexes (Hershko et al., 2005
). Since three molecules of deferiprone are required to completely remove iron from the labile pool, low levels of deferiprone can leave iron incompletely chelated and may cause the unbound portion of iron to be an even more effective catalyst for the generation of free radicals. Given that side effects may be avoidable by careful monitoring and the evidence for efficacy in Friedreich’s Ataxia, L1 may be a promising candidate for the long-term reduction of iron for the prevention or treatment of AMD, and its potential to reduce retinal degeneration due to iron- mediated oxidative stress will be studied in animal models.
Deferasirox (Exjade) is a novel iron chelator that has just been recently approved for clinical use in patients with iron overload due to blood transfusion. Deferasirox is orally active and has an extended half- life, allowing for once-daily oral dosing (Vanorden and Hagemann, 2006
). Due to its relatively small size (MW 373.4), it is well absorbed and shows a two- to fivefold increased potency over deferoxamine for the mobilization of iron from tissue both in vitro
and in vivo
(Galanello et al., 2003
). Current data show deferasirox to be as effective an iron chelator as subcutaneous deferoxamine, which is the current drug of choice for chronic iron overload patients (Piga et al., 2002
). Clinical trials so far have shown deferasirox to have minimal side effects, with nausea, abdominal pain, diarrhea, and skin rash being the most serious and common side effects (Maxton et al., 1986
). Deferasirox is another promising candidate for the long-term reduction of iron for the prevention or treatment of AMD, and its potential to reduce retinal degeneration due to iron- mediated oxidative stress will be studied in animal models.
Another potentially therapeutic iron chelator with interesting properties is salicylaldehyde isonicotinyl hydrazone (SIH). This chelator has excellent cell permeability because of its lipophilicity. It has thus far proven non-toxic in animals (Klimtova et al., 2003
). SIH can protect cultured cardiomyocytes from oxidative stress induced death at concentrations 1000 fold lower than DFO (Simunek et al., 2005
). In our experiments with cultured RPE cells, SIH affords nearly complete protection to ARPE-19 cells against hydrogen peroxide toxicity (Amado D, et al. IOVS
2006;47:ARVO E-Abstract 2081) and can even protect the cells against insults that are not oxidants (Lukinova, N., Dentchev, T., and Dunaief J.L., unpublished). We plan to extend these preliminary in vitro
studies, then test the ability of SIH to protect ceruloplasmin/hephaestin deficient mice from their iron overload induced retinal degeneration.