Drug Trinity Shows Unexpected Strength

Jean-Pierre Julien—his “cocktail” does wonders for ALS mice.

A “cocktail” of three prescription drugs significantly prolongs life and improves strength in a standard mouse model of ALS, a Center research team reports. The new study suggests that pooling drugs, a tactic which has worked so well for HIV patients, is worth a try for this disease.

Most mice on the drug combo lived six weeks longer than their non-drug littermates—a notable increase in animals that typically survive under a year. “And a number of the mice lived much longer than that,” says biochemist Jean-Pierre Julien, who led the team. The cocktail also slowed loss of muscle strength and onset of other ALS-like symptoms in the mice by a month. “Together,” he says, “the drugs show a clear neuroprotective effect.

“We’ve evidence from earlier work that the mix is better than the single drugs would be on their own. There’s likely a synergy of some sort among them.”

Minocycline, riluzole and nimodipine are presently available by prescription for a variety of conditions. Physicians prescribe minocycline, an antibiotic, for infections, though its effect in the model mice isn’t due to its bacteria-fighting capabilities. Nimodipine lowers blood pressure and is believed to lessen brain damage in certain stroke patients. It’s also common for migraine headaches. Only riluzole is aimed at ALS—it’s the only FDA-approved drug for the disease, though its effect in humans and in mouse models is modest.

"We’re quite excited by these results. they support the principle of multi-drug treatment for ALS.

“We picked the three drugs because each targets a different abnormal cell pathway in ALS,” says Julien. Minocycline may work by lessening inflammation or by blocking a cell’s cascade of self-destructing reactions. Nimodipine works to slow abnormal calcium movement in cells, and riluzole likely damps down abnormal release of a nerve transmitter, glutamate, that can be toxic.

In the study, SOD1 mouse models of ALS ate animal chow laced with the three drugs before the time that disease symptoms typically appear. Mice were monitored for muscle weakness and changes in behavior. Later, the team compared numbers of motor nerve cells in the spinal cords of treated animals with those of untreated. They tested for molecules that signal cell death cascades have been turned on. Finally, they checked for an increase in inflammation-linked cells called microglia.

All signs of disease were lessened or delayed in the treated mice.

“We’re quite excited by these results,” says Julien, “and we believe they support the principle of multi-drug treatment for ALS. They should encourage more study.”

The team’s work appears in the March issue of Annals of Neurology.

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