Thalassemia is a blood disorder requiring lifelong transfusions for survival. Erythrocytes accumulate toxic iron at their membranes, triggering an oxidative cascade that leads to their premature destruction. We hypothesized that removing this proximate iron compartment as a primary treatment using novel iron chelators, could prevent hastened red cell removal and clinically alleviate the need for transfusion. Novel, highly cell permeable iron chelators, pyridoxal isonicotinoyl hydrazone (PIH) and pyridoxal ortho-chlorobenzoyl hydrazone (o-108) were compared to the present mainstay, desferrioxamine (DFO) and deferiprone (L1), in vitro and in vivo . Treatment of human model beta-thalassemic erythrocytes with chelators resulted in significant depletion of membrane-associated iron and reduced oxidative stress as indicated by a decrease in methemoglobin levels. When administered to beta-thalassemic mice, iron chelators mobilized erythrocyte membrane iron, reduced cellular oxidation, and prolonged erythrocyte survival. Consistently, these mice showed improved hematological abnormalities. A beneficial effect as early as the erythroid precursor stage was also determined by normalized proportions of mature versus immature reticulocytes. Remarkably, all four chelators reduced iron accumulation in target organs. Most importantly, o-108 revealed superior activity, decreasing iron in liver and spleen by ~5-fold and ~2-fold, respectively, compared to DFO. Our study demonstrates that iron chelators ameliorate thalassemia in a human and murine model, and validates their primary use as an alternative to transfusion therapy.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.82433 |
| Date | January 2004 |
| Creators | Szuber, Natasha |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Physiology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002198751, proquestno: AAIMR12548, Theses scanned by UMI/ProQuest. |
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