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Antibiotics protect nerves in mice by turning on genes

06.01.2005


Large, multi-center clinical trial planned in Lou Gehrig’s disease



A family of antibiotics that includes penicillin may help prevent nerve damage and death in a wide variety of neurological diseases, including Lou Gehrig’s disease, dementia, stroke, and epilepsy, Johns Hopkins researchers have found. The antibiotics’ beneficial effects, discovered in experiments in the lab and with mice, are unrelated to their ability to kill bacteria, the researchers report in the Jan. 6 issue of Nature. Instead, the drugs squelch the dangerous side of a brain chemical called glutamate by turning on at least one gene, thereby increasing the number of "highways," or transporters, that remove glutamate from nerves.

"It would be extremely premature for patients to ask for or take antibiotics on their own," says the study’s leader, Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins and a professor of neurology and of neuroscience. "Only a clinical trial can prove whether one of these antibiotics can help and is safe if taken for a long time."


In mice engineered to develop the equivalent of Lou Gehrig’s disease, daily injections of an antibiotic called ceftriaxone, started just as symptoms tend to surface, delayed both nerve damage and symptoms and extended survival by 10 days compared to untreated animals. Lou Gehrig’s disease, or amyotrophic lateral sclerosis (ALS), in people causes progressive weakness and paralysis and ends in death, usually within three to five years of diagnosis. "We’re very excited by these drugs’ abilities," says Rothstein. "They show for the first time that drugs, not just genetic engineering, can increase numbers of specific transporters in brain cells. Because we study ALS, we tested the drugs in a mouse model of that disease, but this is much bigger than ALS. This approach has potential applications in numerous neurologic and psychiatric conditions that arise from abnormal control of glutamate."

A large, multi-center clinical trial planned for the spring will help determine the best dose of and schedule for ceftriaxone in people with ALS, and will measure whether the known risks of long-term antibiotic treatment are worth it, he says. The drug is currently approved by the U.S. Food and Drug Administration and used to treat bacterial infections in the brain.

More than a dozen of penicillin’s relatives, known as beta-lactam antibiotics, were among protective agents identified by a National Institutes of Health-funded project to screen 1,040 Food and Drug Administration-approved drugs for new uses. The newfound ability of these antibiotics to activate glutamate transporters and to protect nerves, and the drugs’ potential therapeutic use in neurological conditions, are covered by patent applications held by Rothstein and Johns Hopkins and licensed to Ruxton Pharmaceuticals Inc.

Of the antibiotics, penicillin protected nerve cells best in laboratory dishes, but ceftriaxone had the best results in mice, probably because it more easily crosses into the brain from the blood, the researchers report.

Rothstein and his colleagues determined that the antibiotics’ benefit stems from their newly recognized effect on glutamate’s Jekyll-and-Hyde effects. In the brain, glutamate normally excites nerves so that electrical signals can travel from one to the next. But too much of the chemical can overstimulate and kill nerves, a factor in ALS and some other diseases.

In a series of experiments, the researchers discovered that the antibiotics activate the gene encoding glutamate’s main transporter in brain cells. Rats and mice that received daily ceftriaxone for up to a week had triple the usual amount of the transporter, known as GLT1, in their brain cells, an effect that lasted for up to three months after treatment. "Glutamate is just one of many messengers brain cells use to communicate with one another, and this is just one of the transporters that move glutamate," says Rothstein. "So if you can find the right drug, you might be able to specifically affect other transporters, too."

Because ceftriaxone only protects against glutamate damage, just one problem in ALS, it’s not surprising that the mice eventually succumbed to weakness and paralysis despite treatment, he says. "If we can find drugs that protect against other causes of nerve death in ALS, the combination might offer a real therapy, much like using drug combinations to treat cancer," says Rothstein. "The more we know about ALS and other neurological diseases, the better our chances of finding ways to prevent nerve death by all causes."

The research was funded by the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association and the Robert Packard Center for ALS Research at Johns Hopkins. The ALS mice were provided by Project ALS.

Authors of the paper are Rothstein, Sarubhai Patel, Melissa Regan, Christine Haenggeli, Yanhua Huang, Dwight Bergles, Lin Jin, Margaret Dykes Hoberg, Svetlana Vidensky, Dorothy Chung and Shuy Vang Toan, all of Johns Hopkins; Lucie Bruijn of The ALS Association; and Zao-zhong Su, Pankaj Gupta and Paul Fisher of Columbia University Medical Center.

Joanna Downer | EurekAlert!
Further information:
http://www.jhmi.edu
http://www.nature.com/nature

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