Role of oxidative stress in paraquat‐induced dopaminergic cell degeneration

Abstract

Systemic treatment of mice with the herbicide paraquat causes the selective loss of nigrostriatal dopaminergic neurons, reproducing the primary neurodegenerative feature of Parkinson's disease. To elucidate the role of oxidative damage in paraquat neurotoxicity, the time-course of neurodegeneration was correlated to changes in 4-hydroxy-2-nonenal (4-HNE), a lipid peroxidation marker. When mice were exposed to three weekly injections of paraquat, no nigral dopaminergic cell loss was observed after the first administration, whereas a significant reduction of neurons followed the second exposure. Changes in the number of nigral 4-HNE-positive neurons suggest a relationship between lipid peroxidation and neuronal death, since a dramatic increase in this number coincided with the onset and development of neurodegeneration after the second toxicant injection. Interestingly, the third paraquat administration did not cause any increase in 4-HNE-immunoreactive cells, nor did it produce any additional dopaminergic cell loss. Further evidence of paraquat-induced oxidative injury derives from the observation of nitrotyrosine immunoreactivity in the substantia nigra of paraquat-treated animals and from experiments with ferritin transgenic mice. These mice, which are characterized by a decreased susceptibility to oxidative stress, were completely resistant to the increase in 4-HNE-positive neurons and the cell death caused by paraquat. Thus, paraquat exposure yields a model that emphasizes the susceptibility of dopaminergic neurons to oxidative damage.

Oxidative stress and dopamine depletion in an intrastriatal 6-hydroxydopamine model of Parkinson’s disease

“…Silver staining for neurodegeneration was not detected until 24 hours, peaked at 72 hours, and persisted through 120 hours. Similar results were seen from a time course study investigating oxidative stress and neurodegeneration using the paraquat model of PD (McCormack et al, 2005). These studies suggest that markers of oxidative stress are increased before neuronal degeneration is detected.…”

Paraquat and Parkinson's disease

“…Further evidence that oxidative stress is the predominant mechanism by which PQ causes toxicity is the generation of 4-hydroxynonenals in vivo. 27 It is possible to conclude from these studies that the mechanisms of toxicity of PQ in neuronal cultures, cell lines and non-neuronal cells (lung, kidney and hepatocytes) are similar. It is clear that a chemical that is capable of triggering redox cycling/oxidative stress will do it regardless of the cellular system in which it operates in the presence of an adequate electron donor.…”

“…PQ (1,1 0 -dimethyl 4,4 0 -bipyridinium in its reduced form) is a member of a chemical class known as bipyridyl derivatives, which includes diquat (1,1 0 -ethylene-2,2 0 -bipyridylium dibromide) and cyperquat that has the same structure as the MPTP metabolite MPP þ (see below). One-electron reduction of PQ [26][27][28][29] probably underlies its toxic effects in the lung after accidental ingestion. Reduced PQ is then rapidly reoxidized to its cation form by molecular oxygen with the formation of superoxide radicals in a classical redox-cycling reaction.…”

Disruption of dopamine transport by DDT and its metabolites

“…These findings are supported by numerous animal studies that have identified potential mechanistic links between pesticides and PD pathogenesis (Betarbet et al, 2000;Bloomquist et al, 2002;Caudle et al, 2005;Hatcher et al, 2007;Kitazawa et al, 2001Kitazawa et al, , 2003McCormack et al, 2005;Miller et al, 1999;Purkerson-Parker et al, 2001;Richardson et al, 2006;Thiruchelvam et al, 2003). Additionally, higher levels of pesticides have been identified in post-mortem PD brains versus age-matched controls (Corrigan et al, 1998(Corrigan et al, , 2000Fleming et al, 1994;Pennell et al, 2006).…”