Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons

• Published in: PloS one 2015-12, Vol.10 (12), p.e0144848-e0144848
• Main Authors: Aguirre, Pabla, Mena, Natalia P, Carrasco, Carlos M, Muñoz, Yorka, Pérez-Henríquez, Patricio, Morales, Rodrigo A, Cassels, Bruce K, Méndez-Gálvez, Carolina, García-Beltrán, Olimpo, González-Billault, Christian, Núñez, Marco T
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - antagonists & inhibitors; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; 2,2'-Dipyridyl - pharmacology; 8-Hydroxyquinoline; Acetylcysteine; Aging; Animals; Antioxidants; Antioxidants (Nutrients); Antioxidants - pharmacology; Apoptosis; Axonogenesis; Basal ganglia; Biology; Brain research; Care and treatment; Cell culture; Central nervous system diseases; Chelating agents; Damage accumulation; Deferoxamine - pharmacology; Dopamine; Dopamine receptors; Dopaminergic mechanisms; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Female; Fibers; G Protein-Coupled Inwardly-Rectifying Potassium Channels - agonists; G Protein-Coupled Inwardly-Rectifying Potassium Channels - biosynthesis; Health aspects; Homeostasis; Hydroxylase; Hydroxyquinoline; Hydroxyquinolines - pharmacology; Hypotheses; Hypoxia; Iron; Iron Chelating Agents - pharmacology; Laboratories; Life assessment; Lipid Peroxidation - drug effects; Male; Medical treatment; Mesencephalon - drug effects; Mesencephalon - metabolism; Mesencephalon - pathology; Mice; Mice, Inbred C57BL; Model testing; Movement disorders; MPP; MPTP; MPTP Poisoning - drug therapy; MPTP Poisoning - metabolism; MPTP Poisoning - pathology; Nerve Fibers - drug effects; Nerve Fibers - metabolism; Nerve Fibers - pathology; Nervous system; Neurites - drug effects; Neurites - metabolism; Neurites - pathology; Neurodegeneration; Neurodegenerative diseases; Neurons; Neuroprotective Agents - pharmacology; Oral administration; Oxidative stress; Parkinson disease; Parkinson's disease; Parkinsons disease; Potassium channels (inwardly-rectifying); Primary Cell Culture; Pyridones - pharmacology; Rats; Rats, Sprague-Dawley; Rodents; Synaptophysin; Synaptophysin - agonists; Synaptophysin - biosynthesis; Trees; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - biosynthesis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0144848

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.