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Oxidative stress has been implicated in aging and dementia. Oxidative damage and free radicals are thought to cause dementia by killing nerve cells in brain regions responsible for memory, learning and executive function. Antioxidants may prevent or delay the progression of AD and dementia; in fact, epidemiological studies and one clinical trial have indicated that antioxidants such as vitamin E may be useful in preventing and/or possibly treating Alzheimer’s disease. Vitamin E and vitamin C are the most widely used antioxidants but they have considerable disadvantages such as poor penetration into the brain. Thus, there is a need for new, more effective antioxidants. The enzyme extracellular superoxide dismutase (EC-SOD) is one of the most effective mechanisms for preventing oxidative damage. Dr. Levin and others have found that increased EC-SOD activity is therapeutically useful in protecting against oxidative stress induced neurotoxicity. In addition, chronically increased EC-SOD activity has been found to protect against oxidative-stress induced cognitive decline in rodents. Unfortunately, enzyme therapy has limited utility. To remedy this, Dr. Levin and colleagues have developed novel, small molecule mimetics of EC-SOD that protect against oxidative stress induced neurotoxicity. In this pilot- program Dr. Levin will initiate studies to determine the therapeutic potential of the EC-SOD mimetics in aged rodents. If successful this pilot-program will lead to further studies validating the use of EC-OSD mimetics in oxidative stress induced cognitive impairment and may eventually lead to further development of these mimetics as therapeutics for the treatment of AD,and normal age-associated cognitive decline.