Oxidative stress in neurodegenerative diseases: therapeutic implications for superoxide dismutase mimetics.
Evidence of oxidative stress is apparent in both acute and chronic neurodegenerative diseases, such as stroke, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Increased generation of reactive oxygen species simply overwhelm endogenous antioxidant defences, leading to subsequent oxidative damage and cell death. Tissue culture and animal models have been developed to mimic some of the biochemical changes and neuropathology found in these diseases. In doing so, it has been experimentally demonstrated that oxidative stress plays a critical role in neuronal cell death. Antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) have demonstrated therapeutic efficacy in models of neurodegeneration. However, delivery and stability issues have reduced the enthusiasm to clinically develop these proteins. Most recently, SOD mimetics, small molecules which mimic the activity of endogenous superoxide dismutase, have come to the forefront of antioxidant therapeutics. This review will examine the experimental evidence supporting the use of scavengers of superoxide anions in treating some neurodegenerative diseases, such as stroke, PD and ALS, but also the pitfalls that have met antioxidant molecules in clinical trials.
Pong
Kevin
K
Department of Neuroscience, Wyeth Research, Princeton, NJ 08543, USA. pongk@wyeth.com
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D018716:Molecular Mimicry; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000628:therapy*; D018384:Oxidative Stress / Q000502:physiology*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*
D000975:Antioxidants; D013482:Superoxide Dismutase