Oxidative stress in Parkinson's disease: a mechanism of pathogenic and therapeutic significance

Abstract

Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, time-course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death-related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.