Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis.
Dominant mutations in the copper/zinc superoxide dismutase (SOD1) gene have been observed in 15-20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism by which SOD1 mutations result in motor neuron degeneration in FALS mice partly involves oxidative damage and an increased peroxidase activity of the mutant SOD1. A new therapeutic approach designed to eliminate the substrate of this peroxidase activity was examined in two lines of transgenic mice expressing the FALS-linked mutation glycine to alanine (G93A). We investigated the ability of putrescine-modified catalase (PUT-CAT), an antioxidant enzyme that removes hydrogen peroxide and has increased permeability at the blood-brain barrier, to modify the time course of the SOD1 mutation-induced motor neuron disease in these FALS mice. Continuous, subcutaneous administration of PUT-CAT significantly delayed the age at which onset of clinical disease occurred (indicated by loss of splay and/or tremors of hindlimbs) in a high-expressor line of FALS transgenic mice. Intraperitoneal injection of PUT-CAT given two times per week also significantly delayed the onset of clinical disease in a low-expressor line of FALS mice. PUT-CAT also significantly delayed the age at which clinical weakness developed (quantified by measuring the shortening of stride length) in both lines of FALS animals. No significant changes were observed in the survival times of the high-expressor FALS mice in any of the treatment groups. However, a trend toward a prolongation of survival was observed in the PUT-CAT-treated low-expressor FALS mice. These results support the role of free radical-mediated damage in the cascade of events leading to motor neurodegeneration in FALS and indicate that PUT-CAT interacts with a critical step in this cascade to delay the onset of clinical disease as well as the development of clinical weakness in FALS transgenic mice.
Reinholz
M M
MM
Department of Neurology and, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA.
Merkle
C M
CM
Poduslo
J F
JF
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001812:Blood-Brain Barrier; D002021:Buffers; D002374:Catalase / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology; D018908:Muscle Weakness / Q000188:drug therapy / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics; D010710:Phosphates; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics; D016019:Survival Analysis
D000975:Antioxidants; D002021:Buffers; D005609:Free Radicals; D010710:Phosphates; D002374:Catalase; D013482:Superoxide Dismutase; D011700:Putrescine