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 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.
Melov
S
S
Buck Institute for Age Research, Novato, California 94945, USA. smelov@buckinstitute.org
Doctrow
S R
SR
Schneider
J A
JA
Haberson
J
J
Patel
M
M
Coskun
P E
PE
Huffman
K
K
Wallace
D C
DC
Malfroy
B
B
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D002374:Catalase; D002384:Catalysis; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005029:Ethylenediamines / Q000008:administration & dosage / Q000737:chemistry; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000737:chemistry; D007274:Injections, Intraperitoneal; D008055:Lipids / Q000737:chemistry; D008665:Metalloporphyrins / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D012459:Salicylates / Q000008:administration & dosage / Q000737:chemistry; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D015996:Survival Rate; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D002374:Catalase; D005029:Ethylenediamines; D016166:Free Radical Scavengers; D008055:Lipids; D008665:Metalloporphyrins; D009942:Organometallic Compounds; D012459:Salicylates; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C433928:EUK-134; C436526:EUK-189; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II)