Reactive Oxygen and Nitrogen Species: Weapons of Neuronal Destruction in Models of Parkinson's Disease

Parkinson's disease (PD) is a common neurodegenerative disease whose etiology and pathogenesis remain mainly unknown. To investigate its cause and, more particularly, its mechanism of neuronal death, numerous in vivo experimental models have been developed. Currently, both genetic and toxic models of PD are available, but the use of neurotoxins such as 6-hydroxydopamine, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and rotenone are still the most popular means for modeling the destruction of the nigrostriatal dopaminergic neurons seen in PD. These four neurotoxins, although distinct in their intimate cytotoxic mechanisms, kill dopaminergic neurons via a cascade of deleterious events that consistently involves oxidative stress. Herein, we review and compare the molecular mechanisms of 6-hydroxydopamine, paraquat, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, and rotenone, placing the emphasis of our discussion on how reactive oxygen and nitrogen species contribute to the neurotoxic properties of these four molecules. As the reader will discover, to achieve the above stated goal, we had to not only appraise recent findings, but also revisit earlier landmark studies to provide a comprehensive view on this topic. This approach also enabled us to describe how our understanding of the mechanism of actions of certain toxins has evolved over time, which is particularly striking in the case of the quatrogenarian neurotoxin, 6-hydroxydopamine.