Efficient three-drug cocktail for disease induced by mutant superoxide dismutase.

Publication Type:

Journal Article

Authors:

Jasna Kriz; Gowing, Geneviève; J-P Julien

Source:

Ann Neurol, Volume 53, Issue 4, p.429-36 (2003)

Keywords:

Age of Onset, Amyotrophic Lateral Sclerosis, Animals, Anti-Bacterial Agents, Axons, Calcium Channel Blockers, Caspase 3, Caspases, Cyclin-Dependent Kinase 5, Cyclin-Dependent Kinases, Disease Models, Animal, Drug Therapy, Combination, Gliosis, Mice, Mice, Transgenic, Microglia, Minocycline, Motor Neurons, Muscle Contraction, Neuroprotective Agents, Nimodipine, Riluzole, Superoxide Dismutase

Abstract:

<p>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.</p>