Each day, about fifteen people are diagnosed with amyotrophic lateral sclerosis (ALS) in the United States alone. Unfortunately, the size of the pharmaceutical armamentarium that is presently available for the treatment of this fatal neurodegenerative disease in no way reflects that of the patient population. Riluzole — a glutamate antagonist — is the only FDA-approved drug that ameliorates the progression of ALS, and it is often used in conjunction with the muscle-strengthening dietary supplement creatine. Two new papers showcase important data on the effectiveness of these compounds in the treatment of ALS.

The widespread use of creatine by ALS sufferers is based largely on results from a mouse model of the disease in which human mutated superoxide dismutase (SOD) is overexpressed. Creatine monohydrate protects motor neurons against degeneration and significantly prolongs survival of these mutants. But the effect of creatine supplementation on ALS progression in humans had not been evaluated until a Dutch consortium published the results of their double-blind, placebo-controlled sequential clinical trial in a recent issue of the Annals of Neurology.

Disappointingly, the group found no significant effect of creatine on survival or on the rate of functional decline of riluzole-treated patients. This outcome indicates that the pathological mechanisms of ALS might be fundamentally different in mouse models and affected humans.

Nevertheless, the murine SOD1 mutant model of ALS is one of the best available at present, and new hopes have been raised following the discovery by Jasna Kriz and colleagues that a combination of three drugs substantially delays the onset of symptoms and increases average longevity in this model. Working on the hypothesis that multiple pathways contribute to ALS pathogenesis, Kriz et al. targeted three distinct putative pathological mechanisms — the release of proinflammatory molecules from activated microglia, glutamate-mediated excitotoxicity and increased intracellular calcium concentrations — using co-administration of minocycline, riluzole and nimodipine, respectively.

As minocycline and nimodipine are already approved for other conditions, any potential benefits of their combination with riluzole could be assessed in ALS patients relatively rapidly. Hopefully, this three-drug cocktail will not suffer the same fate as creatine in the transition from mouse to man.