Design and evaluation of bi-functional iron chelators for protection of dopaminergic neurons from toxicants

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.

The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis

“…However, PBT2 did not show any significant effect on cognition. Currently, deferiprone (DFP), a compound that alleviates symptoms related to PD pathology (Devos et al, 2014;Grolez et al, 2015;Gutbier et al, 2020), is evaluated a in phase 2 randomized placebo-controlled clinical trial with AD patients (NCT03234686). As previously reported, iron chelators can attenuate symptoms and slow down the progression of AD, which shows the potential for novel therapeutic approaches (Nuñez and Chana-Cuevas, 2018).…”

Probenecid Increases the Concentration of 7-Chlorokynurenic Acid Derived from the Prodrug 4-Chlorokynurenine within the Prefrontal Cortex

“…Cells were then incubated with either 1 mM leucine, 4-Cl-KYN, or 7-Cl-KYNA for 3 min. The uptake was then stopped by washing cells in ice-cold transport buffer . Cells were then incubated in 5% SDS for 15 min at 37 °C.…”

“…The uptake was then stopped by washing cells in ice-cold transport buffer. 24 Cells were then incubated in 5% SDS for 15 min at 37 °C. The lysate was collected, and scintillation fluid was added.…”

Ferroptosis: A potential therapeutic target for neurodegenerative diseases

“…Additionally, it has structural components that allow it to enter the brain via neutral amino acid transporter LAT1. [ 101 ] Moxibustion has shown neuroprotective effects in PD by its anti‐ferroptosis activity. In moxibustion‐treated rats, GPX4 and ferritin heavy chain 1 are overexpressed.…”