Minocycline Delays Onset and Slows Progression of ALS in Mice

For release: Thursday, May 02, 2002

The antibiotic minocycline delays onset and slows progression of symptoms in a mouse model for amyotrophic lateral sclerosis (ALS), a new study shows. The study also revealed that the drug may work by blocking release of a molecule that triggers cell death. The findings may lead to new ways of treating ALS or other neurodegenerative disorders.

ALS, also called Lou Gehrig's disease, is a progressive and fatal neurological disease that attacks the nerve cells responsible for controlling movement. More than 5000 people in the United States are diagnosed with ALS each year. Most patients die within 3 to 5 years after symptoms begin.

Previous studies have shown that minocycline protects neurons from dying in animal models for a variety of disorders, including Huntington's disease, Parkinson's disease, stroke, and traumatic brain injury, and it is currently being tested in human clinical trials of Huntington's disease. However, until now researchers did not know how the drug prevented cell death. The new study shows that minocycline prevents release of a mitochondrial protein called cytochrome c into the body of the cell. Mitochondria are tiny rod-shaped compartments within cells that break down food and produce energy. Release of cytochrome c activates an enzyme that enables cells to commit suicide and is a common feature of many neurological disorders. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the May 2, 2002, issue of Nature .

Researchers led by Robert M. Friedlander, M.D., of Brigham and Women's Hospital in Boston, injected minocycline into mice with mutations, or abnormalities, in the gene for an enzyme called superoxide dismutase-1 (SOD1). Another group of mice received saline (salt water) injections. SOD1 mutations are found in about 20 percent of patients with familial ALS; mice with these mutations develop nerve damage and neurological symptoms that resemble the human disease. The researchers found that minocycline delayed the onset of movement problems in the mouse model by an average of several weeks. The minocycline-treated mice also lived slightly longer than the saline-treated mice.

The researchers also tested the effects of minocycline on neurons in culture and on isolated mitochondria. These studies indicate that minocycline inhibited cell death by preventing release of cytochrome c . Minocycline also significantly inhibited release of cytochrome c in the SOD1 mice. A previous report had shown that release of cytochrome c in spinal cords of these mice correlates with progression of the disease.

The effect of minocycline on survival in the SOD1 mice is roughly equivalent to that of riluzole, the only drug currently approved by the Food and Drug Administration (FDA) to treat ALS, says Dr. Friedlander. In humans, riluzole extends survival by approximately 3 months. However, the new study shows that minocycline works in a very different way than riluzole, which inhibits release of the neurotransmitter glutamate. This suggests that a combination of riluzole and minocycline may be more effective than either drug alone, Dr. Friedlander says. The researchers plan to test combinations of minocycline and other drugs in animals to see if they can identify a drug combination, or "cocktail," that would be a safe, powerful therapy for ALS.

Minocycline is the first non-toxic drug with a proven human safety record that has been shown to inhibit cytochrome c release, says Dr. Friedlander. It also crosses the blood-brain barrier and is effective when taken orally, which makes it a good candidate for human clinical trials. Knowing how minocycline works also will help researchers design and test similar drugs that may be more effective against ALS and other neurological diseases.

Reference: Zhu S, Stavrovskaya IG, Drozda M, Kim BYS, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM. "Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice." Nature, May 2, 2002, Vol. 417, No. 6884, pp.74-78.

- By Natalie Frazin

 

Research update:  Results of an NINDS-sponsored phase III randomized, placebo-controlled trial of the drug minocycline to treat ALS were reported in 2007. This study showed that people with ALS who received minocycline had a 25 percent greater rate of decline than those who received the placebo, according to the ALS functional rating scale (ALSFRS-R).    

Date Last Modified: Tuesday, September 09, 2008

---

 

Related Items

Fact Sheet