Antibiotics Protect Nerves in Mice By Turning on Genes

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http://www.hopkinsmedicine.org/Press_releases/2005/01_05_05.html

Wednesday, January 5, 2005

ANTIBIOTICS PROTECT NERVES IN MICE BY TURNING ON GENES

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, s 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, Rothstein, M.D., Ph.D., director of

the Packard Center for ALS Research at s 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 s 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 Packard Center for ALS

Research at s Hopkins. The ALS mice were provided by Project ALS.

Authors of the paper are Rothstein, Sarjubhai Patel, Regan,

Haenggeli, Yanhua Huang, Dwight Bergles, Lin Jin, Margaret Dykes Hoberg,

Svetlana Vidensky, Dorothy Chung and Shuy Vang Toan, all of s Hopkins; Lucie

Bruijn of The ALS Association; and Zao-zhong Su, Pankaj Gupta and Fisher of

Columbia University Medical Center. Patel is now at the University of Montana.