Iron porphyrin treatment extends survival in a transgenic animal model of amyotrophic lateral sclerosis.
Oxidative damage, produced by mutant Cu/Zn superoxide dismutase (SOD1), may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease. A novel approach to antioxidant therapy is the use of metalloporphyrins that catalytically scavenge a wide range of reactive oxygen and reactive nitrogen species. In this study, we examined the therapeutic potential of iron porphyrin (FeTCPP) in the G93A mutant SOD1 transgenic mouse model of ALS. We found that intraperitoneal injection of FeTCPP significantly improved motor function and extended survival in G93A mice. Similar results were seen with a second group of mice wherein treatment with FeTCPP was initiated at the onset of hindlimb weakness-roughly equivalent to the time at which treatment would begin in human patients. FeTCPP-treated mice also showed a significant reduction in levels of malondialdehyde (a marker of lipid peroxidation), in total content of protein carbonyls (a marker of protein oxidation), and increased neuronal survival in the spinal cord. These results therefore provide further evidence of oxidative damage in a mouse model of ALS, and suggest that FeTCPP could be beneficial for the treatment of ALS patients.
Wu
Annie S
AS
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York 10021, USA.
Kiaei
Mahmoud
M
Aguirre
Norberto
N
Crow
John P
JP
Calingasan
Noel Y
NY
Browne
Susan E
SE
Beal
M Flint
MF
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D008161:Lumbosacral Region; D008315:Malondialdehyde / Q000032:analysis / Q000378:metabolism; D008665:Metalloporphyrins / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D010084:Oxidation-Reduction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
D000975:Antioxidants; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; C473248:iron 5,10,15,20-tetrakis-4-carboxyphenylporphyrin; D008315:Malondialdehyde; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase