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

Samuel Ohiomokhare,Francis Olaolorun,Paul L Chazot,Melanie-Jayne R Howes,James Olopade,Amany Ladagu,Funmilayo Olopade,Edward Okello

doi:10.3390/ijms21186719

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)B9 Drosophila 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.

Highlights

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disease, after Alzheimer’s disease, and affects from one to five percent of the world’s elderly population, i.e., over 60 years to over 85 years, respectively [1]
It is thought to be linked more to environmental and epigenetic factors rather than purely genetic factors, as over 90% of PD cases are of sporadic nature, whilst approximately 5−10% are of familial origin, caused by gene mutations [4]
The first set of experiments were designed to explore the dose-dependent effects of vanadium (VD) on a range of immature and mature monoamine neurons in the culture

Summary

Introduction

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disease, after Alzheimer’s disease, and affects from one to five percent of the world’s elderly population, i.e., over 60 years to over 85 years, respectively [1]. Its prevalence has steadily increased in recent times, and this has been proposed to be associated with exposure to environmental toxicants, including heavy metals. Metal dysregulation with a resultant neurodegenerative disease is of great public health concern [2,3]. It is thought to be linked more to environmental and epigenetic factors rather than purely genetic factors, as over 90% of PD cases are of sporadic nature, whilst approximately 5−10% are of familial origin, caused by gene mutations [4]. Single-gene mutations leading to PD can be divided into two types: Autosomal Dominant Parkinson, including the α-synuclein non-A4 component of the amyloid precursor (NAC/α-synuclein) and leucine repeat rich kinase 2 (LRRK2) [5], and Autosomal Recessive Parkinson (AR-JP), including PARKIN, DJ-1, P type ATPase (ATP13A2), and (PTEN)-induced kinase 1 (PINK-1)

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Results