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THREE DRUG COCKTAIL SHOWS CLEAR BENEFIT
IN MOUSE ALS MODELS Most mice receiving the combination lived six weeks longer than their non-drug littermates--a notable extension in animals that typically survive under a year. The cocktail also delayed loss of muscle strength and onset of other ALS-like symptoms in the mice by a month. According to biochemist Jean-Pierre Julien, Ph.D., who led the research team at McGill University in Montreal, "The three drugs together show a clear neuroprotective effect. We have evidence from earlier work that the combination is better than the single drugs would be on their own. So some sort of synergistic effect may be taking place, we believe." The study was supported by a grant from The Robert Packard Center for ALS Research at Johns Hopkins. The three drugs, minocycline, riluzole and nimodipine are presently available for a variety of conditions. Minocycline is a tetracycline antibiotic that Julien says is frequently prescribed for infections. (The study showed, however, that its effect in the model mice isn't because of its usual bacteria-fighting capabilities.) Nimodipine lowers blood pressure and is usually given to people with a brain hemorrhage, to try to lessen brain damage. It's also common as a drug for migraine headaches. Only riluzole is prescribed for ALS--in fact, it's the only FDA-approved drug for the disease, though its effect in humans and in mouse models is modest. "We picked the three drugs because they each target a different cell pathway that's abnormal in ALS," says Julien. Minocycline may do good by lessening inflammation or by blocking a cell's built-in cascade of self-destructing reactions. Nimodipine works to slow abnormal movement of calcium in cells and riluzole likely damps down abnormal release of a nerve transmitter, glutamate that can be toxic to cells. The study followed mouse models with the same human gene that triggers an inherited form of ALS in some patients. The SOD1 gene they carry produces a mutant protein in the animals that somehow prompts motor nerve cell death and symptoms of the disease. The test animals received the three drugs, before any disease symptoms would normally have appeared, by eating specially-prepared animal chow. They were monitored for muscle weakness and changes in behavior. The researchers also compared numbers of motor nerve cells in the spinal cords of treated animals with those of untreated. They tested the animals for appearance of molecules that signal cell death pathways have been turned on. Finally, they checked for an increase in inflammatory cells called microglia, typically seen in the disease. All of the negative signs were lessened or delayed in the treated mice. "We're quite excited by these results," says Julien, "and we believe they could support the principle of multi-drug treatment for ALS. We hope they encourage more study." The team's work appears in the March issue of Annals of Neurology. The Robert Packard Center for ALS Research at Johns Hopkins University, which sponsored the study, is an organization that targets leading investigators worldwide for collaborative work on ALS. Packard Center scientists and clinicians work aggressively and rapidly to develop new treatments and find a cure for amyotrophic lateral sclerosis (ALS). Research conducted by the Center is meant to translate from the laboratory bench to the clinic in record time. It is the only organization and Institution with a proven track record of moving drugs reliably and rapidly from pre-clinical experiments to human trials. Kriz, J., Gowing, G., Julien, J.P. Efficient three-drug
cocktail for disease induced by mutant superoxide dismutase. Published
Online: 14 Feb 2003. Annals of Neurology |
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