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The Journal of Neuroscience, November 1, 2001, 21(21):8348-8353
Lifespan Extension and Rescue of Spongiform Encephalopathy in Superoxide Dismutase 2 Nullizygous Mice Treated with Superoxide Dismutase-Catalase Mimetics
Simon Melov1, Susan R. Doctrow2, Julie A. Schneider3, Joanna Haberson1, Manisha Patel4, Pinar E. Coskun5, Karl Huffman2, Douglas C. Wallace5, and Bernard Malfroy2 1 Buck Institute for Age Research, Novato, California 94945, 2 Eukarion Inc., Bedford, Massachusetts 01730, 3 Rush Alzheimer's Disease Center, Rush Institute for Healthy Aging, Rush-Presbyterian St. Luke's Hospital, Chicago, Illinois 60612, 4 National Jewish Medical Research Institute, Denver, Colorado 80206, and 5 Center for Molecular Medicine, Emory University, Atlanta, Georgia 30322
Superoxide is produced as a result of normal energy metabolism within the mitochondria and is scavenged by the mitochondrial form of superoxide dismutase (sod2). Mice with inactivated SOD2 (sod2 nullizygous mice) die prematurely, exhibiting several metabolic and mitochondrial defects and severe tissue pathologies, including a lethal spongiform neurodegenerative disorder (Li et al., 1995; Melov et al., 1998, 1999). We show that treatment of sod2 nullizygous mice with synthetic superoxide dismutase (SOD)-catalase mimetics extends their lifespan by threefold, rescues the spongiform encephalopathy, and attenuates mitochondrial defects. This class of antioxidant compounds has been shown previously to extend lifespan in the nematode Caenorhabditis elegans (Melov et al., 2000). These new findings in mice suggest novel therapeutic approaches to neurodegenerative diseases associated with oxidative stress such as Friedreich ataxia, spongiform encephalopathies, and Alzheimer's and Parkinson's diseases, in which chronic oxidative damage to the brain has been implicated.
Key words: mitochondria; oxidative stress; superoxide dismutase; antioxidants; neurodegeneration; spongiform encephalopathy
Copyright © 2001 Society for Neuroscience 0270-6474/01/21218348-06$05.00/0
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