oxidative stress and neurodegeneration

neurodegeneration is a complex and multifaceted process leading to many chronic disease states. a conventional definition implies a progressive neuronal death, which usually affects a specific population of nerve cells the vulnerability of which determines the clinical manifestations of a particular neurodegenerative disease. the neurodegenerative process is associated with many events. each event may correspond to a typical feature of a specific disease. the factors that underlie neurodegeneration can be classified as genetic, environmental (extrinsic neurotoxins, e.g. metals, infective damage), biological (aggregation, abnormal folding and accumulation of proteins), metabolic (oxidative stress), excitotoxic (intrinsic neurotoxins, e.g. metals and excitatory amino acids), autoimmunity and aging. oxidative stress is one of the earliest pathological changes which plays a critical role in vascular abnormalities underlying metabolic defects in neurodegenerative diseases. the free radical theory of neurodegeneration and aging hypothesizes a single common process modifiable by genetic and environmental factors in which oxygen-derived free radicals are responsible (due to their high reactivity) for neurodegenerative diseases and the age-associated damage at cellular and tissue levels. in fact, the accumulation of endogenous oxygen radicals generated in cells and the consequent oxidative modification of biological molecules (lipids, proteins and nucleic acids) have been held responsible for aging and death of all living creatures. since endothelial reactive oxygen species act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging can lead to reduced bioavailability and increased oxidative stress that damage sensitive vascular cells. furthermore, chelation therapy could be a valuable therapeutic approach since metals are considered to be a pharmacological target for designing new therapeutic agents directed at the treatment of neurodegeneration. studies that have evaluated agents claimed to be “antioxidant” in animal models in different neurological conditions with strongly implicated oxidative stress components have revealed a generally favorable series of outcomes with antioxidant therapies and have proved to be largely efficacious across models. in contrast, study of the literature regarding the efficacy of antioxidants in human supplementation trials or clinical drug trials have revealed little to no effect for commonly-employed antioxidant substances and no benefit for the most heavily-studied synthetic antioxidant drug candidates tested against stroke. even more disconcerting, there is emerging data that suggests very high-dose or long-term supplementation with vitamin e may pose certain health risks.