Iron accumulation and retinal pathology: neuroprotection by diketopiperazines

Iron is essential for cell survival, albeit excessive iron causes generation of reactive oxygen species, such as hydroxyl radicals, and becomes detrimental for the cells. Abnormal accumulation of brain iron has been detected in various neurodegenerative diseases, including Alzheimer's disease, as well as studies have suggested a role for excessive iron to the pathogenesis of age-related macular degeneration (AMD), a retinal disease showing pathological similarities with Alzheimer's disease. The contribution of iron overload in the brain and retina diseases remains unclear. We analyzed the pathogenesis/progression of the retinal degeneration by injection of Fe3SO4 together with the effects induced by diketopiperazines (DKPs). DKPs are small heterocyclic peptides with high stability against the proteolysis and with properties of antioxidant and neuroprotective agents. Different DKPs chemically modified were tested in our model. Through histopathological and biochemical analyses, we found lipid, protein and DNA oxidation that was accompanied by accumulation of ferric iron as detected by Perl's blue staining. Reactive gliosis and increased levels of TNF-alpha were also detected throughout the retina, while formations similar to the typical drusen of AMD were seen between the Bruch's membrane and the retinal pigment epithelium. Pre- or post-treatments with DKPs resulted in the retinal protection against iron overload-induced damage. We conclude that our model recapitulates AMD signs of degeneration and DKPs may be a new therapeutic strategy to further pursue.