The Role of Iron Toxicity in Oxidative Stress-induced Cellular Degeneration in Down Syndrome: Protective Effects of Phenolic Antioxidants

A chronic oxidative stress is a typical feature of Down Syndrome (DS, trisomy 21), the major cause of mental disability in humans. In this paper we report the first experimental evidence that iron toxicity may contribute to build up the pro-oxidative microenvironment that characterizes trisomic tissues, using intact erythrocytes as the model system. Blood samples were obtained from trisomic patients and healthy controls in paediatric age. When DS erythrocytes are subjected to oxidative treatment in vitro, the increase in reactive oxygen species (ROS) is higher compared to control cells. Interestingly, incubation with iron chelator deferoxamine results in reduced ROS generation, the decrease being greater in DS erythrocytes than in control cells. Furthermore, we examine the possible protective effect of phenolic antioxidants, including olive oil hydroxytyrosol (HT) and its methoxy analogue homovanillyl alcohol (MeHT), displaying similar scavenging activities, and whether the protective effects could also be related to metal chelating properties. We report that both compounds significantly decrease oxidative stress-induced ROS generation at the concentration range utilized (10-50 μM), HT being more active than MeHT, likely due to its scavenging and iron chelating activities. Similar data are reported for protection against lipoperoxidation. Therefore, HT represents a good candidate for novel dietary and/or nutraceutical strategies of potential therapeutic benefit in DS. The hypothesis that intraerythrocyte iron accumulation could signal increased Alzheimer's Disease risk in DS, and the possible pathophysiological implications, are also discussed.