Abstract
While the etiology of non-familial Parkinson’s disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We, therefore, designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10–20 µM blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). Rescue was also observed when chelators were given after the toxicant. SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly support the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD), affecting 1–2% of the population over 65 years of age
We found in an additional experiment that SK4 and DFP rescued dopaminergic neurons even when applied 2 h after the toxicant (Fig. S8)
We present data on the physicochemical characterization as well as cellular investigations of novel iron chelators produced in our laboratories
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD), affecting 1–2% of the population over 65 years of age (de Rijk et al 2000). As iron promotes the generation of highly aggressive free radicals via the Haber–Weiss cycle/Fenton reaction (Schildknecht et al 2013), abnormal accumulation of redox-active metal in the brain could play a central role in PD neuropathology In this regard, it was suggested that oxidation of iron to the ferric state may drive a vicious circle between excessive pathological levels of reactive oxygen species (ROS), and the intracellular deposition of aggregated α-SYN (Febbraro et al 2012; Levin et al 2009; Schildknecht et al 2013). The therapeutic efficacy of iron chelators against neurodegenerative disease may be further improved by promoting their uptake into the brain and by altering their affinity pattern for various relevant ions With this in mind, we explored the anti-PD therapeutic potential of novel hydroxypyridinones (HOPOs) and related structures (Chaves et al 2018; Workman et al 2015). Our screen revealed strong neuroprotective properties for one novel chelator in particular, the 3-hydroxy-4(1H)-pyridinone termed SK4, which validates abnormal levels of iron ions as a target for the development of novel therapeutic approaches for slowing PD-related neurodegeneration
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