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.