title: Lipophilic adamantyl- or deferasirox-based conjugates of desferrioxamine B have enhanced neuroprotective capacity: implications for Parkinson disease.
abstract: Parkinson disease (PD) is a neurodegenerative disease characterized by death of dopaminergic neurons in the substantia nigra region of the brain. Iron content is also elevated in this region in PD and is implicated in the pathobiology of the disease. Desferrioxamine B (DFOB) is a high-affinity iron chelator and has shown efficacy in animal models of Parkinson disease. The high water solubility of DFOB, however, attenuates its ability to enter the brain. In this study, we have conjugated DFOB to derivatives of adamantane or the clinical iron chelator deferasirox to produce lipophilic compounds designed to increase the bioavailability of DFOB to brain cells. We found that the novel compounds are highly effective in preventing iron-mediated paraquat and hydrogen peroxide toxicity in neuronal-like BE2-M17 dopaminergic cells, primary neurons, and iron-loaded or glutathione-depleted primary astrocytes. The compounds also alleviated paraquat toxicity in BE2-M17 cells that express the PD-causing A30P mutation of α-synuclein. This protection was ∼66-fold more potent than DFOB alone and also more effective than other cell-permeative metal chelators, clioquinol and phenanthroline. These results demonstrate that increasing the bioavailability of DFOB through the conjugation of lipophilic fragments greatly enhances its protective capacity. These novel compounds have potential as therapeutics for the treatment of PD and other conditions of Fe dyshomeostasis.
authors: Department of Pathology, University of Melbourne, and Mental Health Research Institute, Melbourne Brain Centre, University of Melbourne, Parkville, VIC 3010, Australia. jliddell@unimelb.edu.au
authors: Jeffrey R
authors: JR
authors: Liddell
authors: Daniel
authors: D
authors: Obando
authors: Joe
authors: J
authors: Liu
authors: George
authors: G
authors: Ganio
authors: Irene
authors: I
authors: Volitakis
authors: Su San
authors: SS
authors: Mok
authors: Peter J
authors: PJ
authors: Crouch
authors: Anthony R
authors: AR
authors: White
authors: Rachel
authors: R
authors: Codd
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001565:Benzoates / Q000008:administration & dosage* / Q000737:chemistry; D002478:Cells, Cultured; D000077588:Deferasirox; D003676:Deferoxamine / Q000008:administration & dosage* / Q000737:chemistry; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy*; D010539:Permeability / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D014230:Triazoles / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D014230:Triazoles; D006861:Hydrogen Peroxide; D003676:Deferoxamine; D000218:Adamantane; D000077588:Deferasirox