Oxidative stress and nitration in neurodegeneration: cause, effect, or association?

Abstract

Oxidation and nitration of proteins, DNA, and lipids are markers of neurodegeneration in postmortem tissues. It is impossible to determine with certainty using postmortem analysis, whether oxidative stress has a primary role in neurodegeneration or is a secondary end-stage epiphenomenon. Growing evidence suggests that the generation of oxidants does not result simply from an accidental disruption of aerobic metabolism, but rather from an active process crucial for the nonspecific immune defenses of the brain. While essential for survival, these processes may be inappropriately activated to cause neurodegeneration. Neurons are highly susceptible to oxidative stress, which can induce both neuronal necrosis and apoptosis. Oxidants may also have more subtle roles in compromising the integrity of the bloodbrain barrier and in producing reactive changes in astrocytes that further propagate injury. Moreover, oxidative stress appears to provide a critical link between environmental factors, such as exposure to pesticides, herbicides, and heavy metals, and endogenous and genetic risk factors in the pathogenic mechanisms of neurodegeneration, particularly in Parkinson disease. Here, we discuss some recent insights into the diverse roles and controversies about the role of oxidants in neurodegeneration. A better understanding of the role of oxidants in neurodegeneration still holds a largely unfulfilled potential to reduce the burden of both acute and chronic neurodegeneration.