The Pathopharmacological Interplay between Vanadium and Iron in Parkinson’s Disease Models

Abstract

Parkinson’s disease (PD) pathology is characterised by distinct types of cellular defects, notably associated with oxidative damage and mitochondria dysfunction, leading to the selective loss of dopaminergic neurons in the brain’s substantia nigra pars compacta (SNpc). Exposure to some environmental toxicants and heavy metals has been associated with PD pathogenesis. Raised iron levels have also been consistently observed in the nigrostriatal pathway of PD cases. This study explored, for the first time, the effects of an exogenous environmental heavy metal (vanadium) and its interaction with iron, focusing on the subtoxic effects of these metals on PD-like oxidative stress phenotypes in Catecholaminergic a-differentiated (CAD) cells and PTEN-induced kinase 1 (PINK−1)B9Drosophila melanogaster models of PD. We found that undifferentiated CAD cells were more susceptible to vanadium exposure than differentiated cells, and this susceptibility was modulated by iron. In PINK−1 flies, the exposure to chronic low doses of vanadium exacerbated the existing motor deficits, reduced survival, and increased the production of reactive oxygen species (ROS). Both Aloysia citrodora Paláu, a natural iron chelator, and Deferoxamine Mesylate (DFO), a synthetic iron chelator, significantly protected against the PD-like phenotypes in both models. These results favour the case for iron-chelation therapy as a viable option for the symptomatic treatment of PD.

Attenuation of Vanadium-Induced Neurotoxicity in Rat Hippocampal Slices (In Vitro) and Mice (In Vivo) by ZA-II-05, a Novel NMDA-Receptor Antagonist

“…Animal studies have provided support for this hypothesis, as evidenced by the significant reduction in vanadium toxicity when antioxidants are administered either concurrently [21] or incorporated as coordination ligands [22]. As mentioned previously, disturbances in NMDAR activity have been linked to neurodegenerative disorders [23,24]. In this current study, we unravel new insights and novel findings that demonstrate the potential of ZA-II-05, a multi-target directed ligand (MTDL), in reversing vanadium-induced neurotoxicity.…”

Biological Consequences of Vanadium Effects on Formation of Reactive Oxygen Species and Lipid Peroxidation

“…Ngwa and coworkers have reported a link between vanadium neurotoxicity and its effect on the dopaminergic system due to its effect on protein kinase C-delta and its function in cell signaling mechanisms [ 227 ]. Ohiomokhare and coworkers (2020) found that vanadium increased ROS and decreased motor function in Melanogaster drosophila, both wild-type and PD models, and that these effects were alleviated with chelators or the administration of L-DOPA [ 228 ].…”

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“…One such heavy metal reported to cause varying toxicities to the brain and, indeed, to a variety of biological systems is vanadium . Vanadium is a transition metal that crosses the blood-brain barrier (Fatola et al 2019) and causes oxidative stress by reactive oxygen species (ROS) generation, lipid peroxidation, demyelination and neuropathologies in nervous tissues (Mustapha et al 2014(Mustapha et al , 2019bAzeez et al 2016;Folarin et al 2017;Ohiomokhare et al 2020;Olaolorun et al 2021). It is released in high atmospheric concentrations in its gaseous state as vanadium pentoxide, most especially during gas flaring and burning of fossil fuels (Igado et al 2012;Fortoul et al 2014).…”