title: Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons.
abstract: Neuronal death in Parkinson's disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2'-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death.
authors.affiliation: Iron and Biology of Aging Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.|Research Ring on Oxidative Stress in the Nervous System, Santiago, Chile.
authors.forename: Pabla
authors.initials: P
authors.lastname: Aguirre
authors.affiliation: Iron and Biology of Aging Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Mena
authors.affiliation: Iron and Biology of Aging Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.|Research Ring on Oxidative Stress in the Nervous System, Santiago, Chile.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Carrasco
authors.affiliation: Iron and Biology of Aging Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.|Research Ring on Oxidative Stress in the Nervous System, Santiago, Chile.
authors.forename: Yorka
authors.initials: Y
authors.lastname: Muñoz
authors.affiliation: Iron and Biology of Aging Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Patricio
authors.initials: P
authors.lastname: Pérez-Henríquez
authors.affiliation: Iron and Biology of Aging Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Morales
authors.affiliation: Chemobiodynamics Laboratory, Chemistry Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Cassels
authors.affiliation: Chemobiodynamics Laboratory, Chemistry Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Méndez-Gálvez
authors.affiliation: Chemobiodynamics Laboratory, Chemistry Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.|Facultad de Ciencias Naturales y Matemáticas, Universidad de Ibagué, Ibagué, Colombia.
authors.forename: Olimpo
authors.initials: O
authors.lastname: García-Beltrán
authors.affiliation: Research Ring on Oxidative Stress in the Nervous System, Santiago, Chile.|Neuronal and Cellular Dynamics Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.
authors.forename: Christian
authors.initials: C
authors.lastname: González-Billault
authors.affiliation: Iron and Biology of Aging Laboratory, Biology Department, Faculty of Sciences, Universidad de Chile, Santiago, Chile.|Research Ring on Oxidative Stress in the Nervous System, Santiago, Chile.
authors.forename: Marco T
authors.initials: MT
authors.lastname: Núñez
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D000077543:Deferiprone; D003676:Deferoxamine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists / Q000096:biosynthesis; D006912:Hydroxyquinolines / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016708:Synaptophysin / Q000819:agonists / Q000096:biosynthesis; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; C497069:Kcnj6 protein, mouse; D018696:Neuroprotective Agents; D011728:Pyridones; D016708:Synaptophysin; C569015:Syp protein, mouse; D000077543:Deferiprone; D015082:2,2'-Dipyridyl; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D003676:Deferoxamine