title: The novel mitochondrial iron chelator 5-((methylamino)methyl)-8-hydroxyquinoline protects against mitochondrial-induced oxidative damage and neuronal death.
abstract: Abundant evidence indicates that iron accumulation, oxidative damage and mitochondrial dysfunction are common features of Huntington's disease, Parkinson's disease, Friedreich's ataxia and a group of disorders known as Neurodegeneration with Brain Iron Accumulation. In this study, we evaluated the effectiveness of two novel 8-OH-quinoline-based iron chelators, Q1 and Q4, to decrease mitochondrial iron accumulation and oxidative damage in cellular and animal models of PD. We found that at sub-micromolar concentrations, Q1 selectively decreased the mitochondrial iron pool and was extremely effective in protecting against rotenone-induced oxidative damage and death. Q4, in turn, preferentially chelated the cytoplasmic iron pool and presented a decreased capacity to protect against rotenone-induced oxidative damage and death. Oral administration of Q1 to mice protected substantia nigra pars compacta neurons against oxidative damage and MPTP-induced death. Taken together, our results support the concept that oral administration of Q1 is a promising therapeutic strategy for the treatment of NBIA.
authors.affiliation: Iron and Biology of Aging Laboratory, Department of Biology, Faculty of Sciences, University of Chile, Chile. Electronic address: natalia.paz.menaj@gmail.com.
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Mena
authors.affiliation: Facultad de Ciencias Naturales y Matemáticas, Universidad de Ibagué, Ibagué 730001, Colombia.
authors.forename: Olimpo
authors.initials: O
authors.lastname: García-Beltrán
authors.affiliation: Iron and Biology of Aging Laboratory, Department of Biology, Faculty of Sciences, University of Chile, Chile.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Lourido
authors.affiliation: Iron and Biology of Aging Laboratory, Department of Biology, Faculty of Sciences, University of Chile, Chile.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Urrutia
authors.affiliation: Iron and Biology of Aging Laboratory, Department of Biology, Faculty of Sciences, University of Chile, Chile.
authors.forename: Raúl
authors.initials: R
authors.lastname: Mena
authors.affiliation: Faculty of Basic Sciences, Universidad Metropolitana de Ciencias de la Educación, Santiago, Chile.
authors.forename: Vicente
authors.initials: V
authors.lastname: Castro-Castillo
authors.affiliation: Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Cassels
authors.affiliation: Iron and Biology of Aging Laboratory, Department of Biology, Faculty of Sciences, University of Chile, Chile.
authors.forename: Marco T
authors.initials: MT
authors.lastname: Núñez
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D012402:Rotenone / Q000494:pharmacology
chemical_list: C000602394:5-((methylamino)methyl)-8-hydroxyquinoline; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D012402:Rotenone; D007501:Iron
keywords: Hydroxyquinolines; Iron chelation; Mitochondria; Parkinson's disease