Efficient three-drug cocktail for disease induced by mutant superoxide dismutase.
There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.
Kriz
Jasna
J
Centre for Research in Neurosciences, McGill University, Research Institute of the McGill University Health Centre, Montréal, Québec H3G 1A4, Canada.
Gowing
Geneviève
G
Julien
Jean-Pierre
JP
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005911:Gliosis / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D008911:Minocycline / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects / Q000648:ultrastructure; D009119:Muscle Contraction / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology*; D019782:Riluzole / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D009553:Nimodipine; D019782:Riluzole; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D008911:Minocycline