Manganese porphyrin given at symptom onset markedly extends survival of ALS mice.
Mice that overexpress the human Cu,Zn superoxide dismutase-1 mutant G93A develop a delayed and progressive motor neuron disease similar to human amyotrophic lateral sclerosis (ALS). Most current studies of therapeutics in these mice to date have involved administration of agents long before onset of symptoms, which cannot currently be accomplished in human ALS patients. We examined the effects of the manganese porphyrin AEOL 10150 (manganese [III] tetrakis[N-N'-diethylimidazolium-2-yl]porphyrin) given at symptom onset and found, in three separate studies, that it extended the survival after onset up to 3.0-fold. Immunohistochemical analysis of spinal cord for SMI-32, an abundant protein in motor neurons, indicated better preservation of motor neuron architecture, less astrogliosis (glial fibrillary acidic protein), and markedly less nitrotyrosine and malondialdehyde in porphyrin-treated spinal cords relative to vehicle-treated mice. These results show that the catalytic antioxidant AEOL 10150 provides a pronounced therapeutic benefit with onset administration and is, therefore, a promising agent for the treatment of ALS.
Crow
John P
JP
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. jpcrow@uams.edu
Calingasan
Noel Y
NY
Chen
Junyu
J
Hill
Julie Lynch
JL
Beal
M Flint
MF
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005609:Free Radicals / Q000737:chemistry / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008665:Metalloporphyrins / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D011897:Random Allocation; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D016019:Survival Analysis
C472668:AEOL 10150; D005609:Free Radicals; D005904:Glial Fibrillary Acidic Protein; D008665:Metalloporphyrins; D016900:Neurofilament Proteins; C051774:neurofilament protein H; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase