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," said the study's
leader, Jeffrey Rothstein, director of the
Robert Packard Center
for ALS Research at Johns Hopkins and a professor of
neurology and of
neuroscience in the School of Medicine. "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, 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,"
Rothstein said. "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 multicenter 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 said. The drug is currently approved by the U.S.
Food and Drug Administration and is 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 FDA-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 — is covered by patent applications held
by Rothstein and Johns Hopkins and licensed to Ruxton
Pharmaceuticals.
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," Rothstein said.
"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 said.
"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," Rothstein said. "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, all of Columbia University
Medical Center.
Under a licensing agreement between Ruxton
Pharmaceuticals and The Johns Hopkins University, Rothstein
is entitled to a share of royalty received by the
university on sales of products described in this study.
Rothstein and the university own Ruxton Pharmaceuticals
stock, which is subject to certain restrictions under
university policy. Rothstein is a paid consultant to Ruxton
Pharmaceuticals. The terms of these arrangements are being
managed by The Johns Hopkins University in accordance with
its conflict-of-interest policies.