Pharmacological and toxicological effects of copper and vanadium using in vitro and in vivo models of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) pathology is characterised by distinct types of cellular defects: notably, oxidative damage and mitochondria dysfunction, leading to selective loss of dopaminergic neurons in the substantia nigra pars compacta. Exposure to heavy metals and some environmental toxicants have been associated for many years with this disease pathogenesis. Raised iron levels have been consistently observed in the nigrostriatal pathway in PD cases. This thesis focused on the effects of an endogenous heavy metal micronutrient (copper - Cu) and an exogenous environmental heavy metal (vanadium - Vd), and explored the interplay with iron (Fe), focusing for the first time on sub-toxic effects of these metals upon neuronal cell oxidative and ER stress, differentiation, calcium signalling, motor activity, oxidative stress and lifespan in an in vitro (Catecholaminergic a-differentiated (CAD) cells) and in vivo (Drosophila melanogaster) model of PD respectively.
Undifferentiated CAD cells were more susceptible to vanadium exposure than differentiated cells and this susceptibility was modulated by iron. Both a natural (Aloysia citrodora) and synthetic iron chelator, Deferoxamine (DFO), significantly and efficiently protected against chronic sub-toxic Vd-induced mitochondrial oxidative stress in contrast, iron chelation exacerbated the oxidative stress elicited by Cu.
Low dose Cu had no significant effect upon metabolic rate (in both differentiated and differentiating CAD cells) but significantly protected undifferentiated cells, decreased potassium chloride (KCl)-induced depolarisation and positively enhanced the expression of MAP2 in differentiated cells
In vivo exposure of Drosophila melanogaster (DM) to sub-toxic doses of Vd had a range of differential biochemical and behavioural effects upon wild-type (WT) and PD Pink-1B9 drosophila fly models. In pink-1 flies, exposure to chronic low dose of vanadium exacerbated the existing motor deficits, reduced survival, increased the production of reactive oxygen species (ROS), as well as T-SH and a reduction in survival. In WT, it caused an enhancement in motor activity (like L-dopa), in parallel with a reduction in brain RONS generation and increased total thiol levels (T-SH), with a resulting lifespan extension. Both Aloysia citrodora L, and DFO significantly protected against the PD-like phenotypes in both models. The results accrued in this thesis favours the case for iron-chelation therapy as a viable option for the symptomatic treatment of PD.