Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics

Superoxide is produced as a result of normal energy metabolism within the m itochondria and is scavenged by the mitochondrial form of superoxide dismut ase (sod2). Mice with inactivated SOD2 (sod2 nullizygous mice) die prematur ely, exhibiting several metabolic and mitochondrial defects and severe tiss ue pathologies, including a lethal spongiform neurodegenerative disorder (L i et al., 1995; Melov et al., 1998, 1999). We show that treatment of sod2 n ullizygous 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 Caenorhabditi s elegans (Melov et al., 2000). These new findings in mice suggest novel th erapeutic approaches to neurodegenerative diseases associated with oxidativ e stress such as Friedreich ataxia, spongiform encephalopathies, and Alzhei mer's and Parkinson's diseases, in which chronic oxidative damage to the br ain has been implicated.