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.
Highlights
A large body of evidence shows that disturbed iron homeostasis, often coupled to mitochondrial dysfunction, plays an important role in the development of common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease [1,2,3].PLOS ONE | DOI:10.1371/journal.pone.0144848 December 14, 2015Iron Chelators Induce Neuritogenesis
Considering that the effect of MPP+ on neuritic tree length most probably depends on the intracellular iron concentration [26], it was of interest to investigate whether commonly used iron chelators could regenerate the axodendritic tree of cultured dopaminergic neurons previously damaged by MPP+
We found that MPTP treatment diminished GIRK2 immunostaining in the nigrostriatal pathway and substantia nigra pars compacta (SNc) neuronal somas, which recovered after M30 treatment (Fig 7A)
Summary
A large body of evidence shows that disturbed iron homeostasis, often coupled to mitochondrial dysfunction, plays an important role in the development of common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease [1,2,3].PLOS ONE | DOI:10.1371/journal.pone.0144848 December 14, 2015Iron Chelators Induce Neuritogenesis. A large body of evidence shows that disturbed iron homeostasis, often coupled to mitochondrial dysfunction, plays an important role in the development of common neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease [1,2,3].
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