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

• Type of Material: Article
• Authors: Simon Melov, Buck Institute for Age Research, Novato; Susan R. Doctrow, Eukarion Inc., Bedford; Julie A. Schneider, Rush-Presbyterian St. Luke's Hospital; Joanna Haberson, Buck Institute for Age Research, Novato; Manisha Patel, Emory University; Pinar E. Coskun, Emory University; Karl Huffman, Eukarion Inc., Bedford; Douglas C. Wallace, Emory University; Bernard Malfroy, Eukarion Inc., Bedford
• Language: English
• Date: 2001-11-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2001 Society for Neuroscience
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.21-21-08348.2001
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 21
• Issue: 21
• Start Page: 8348
• End Page: 8353
• Grant/Funding Information: This work was supported by National Institutes of Health Grants DCW-AG13154, HL45572, NS21328, and AG18679 (S.M.).
• Keywords: HYDROGEN-PEROXIDE; spongiform encephalopathy; CELL-DEATH; Neurosciences & Neurology; oxidative stress; superoxide dismutase; neurodegeneration; antioxidants; PRION PROTEIN; OXYGEN; Neurosciences; OXIDATIVE STRESS; mitochondria; FRIEDREICH ATAXIA; HEART-MITOCHONDRIA; SALEN-MANGANESE COMPLEXES; Life Sciences & Biomedicine; MUTANT MICE; ALZHEIMERS-DISEASE; Science & Technology
• Research Categories: Biology, Neuroscience; Biology, Animal Physiology; Chemistry, Biochemistry

Abstract

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.