What's Old is New Again - Antibiotic Protects Nerves By Removing Excess Glutamate

For release: Monday, February 07, 2005

A new study shows that a common antibiotic used to treat bacterial infections increases survival rates and delays nerve damage in a mouse model for amyotrophic lateral sclerosis (ALS). The antibiotic works by activating or "turning on" the gene encoding the glutamate transporter in neurons.  This finding may lead to new drug treatments for ALS and other neurodegenerative diseases.

Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins University in Baltimore, Maryland , and his colleagues reported the beneficial effects of the antibiotic ceftriaxone in a mouse animal model of ALS in the January 6, 2005, issue of Nature.* Ceftriaxone treatment, started at the onset of the disease in the mouse model, delayed the loss of neurons and muscle strength while increasing survival time.  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

The initial focus on antibiotics for ALS resulted from the NINDS-led Drug Screening Consortium, an effort in which 27 investigators, including Dr. Rothstein, screened 1040 existing drugs to assess their potential to treat a variety of neurodegenerative disorders.  Co-sponsored by The ALS Association and two Huntington's disease groups, the purpose of this cooperative drug screening approach was to use rapid technology to find new uses for existing drugs.  Ceftriaxone was one of the drugs that showed promise for ‘crossing-over' into neurodegenerative diseases.

The potentially therapeutic properties of ceftriaxone for ALS have little to do with its antibiotic effects but instead result from its ability to increase the number of glutamate transporters.  Glutamate transporters are proteins that vacuum up the excitatory neurotransmitter glutamate. Normally, glutamate acts to excite nerves so that electrical signals can travel from one to the next. Too much glutamate has a toxic effect on nerve cells and has been implicated in neurodegenerative diseases such as ALS, Huntington's disease, Alzheimer's disease, epilepsy and stroke. Removing glutamate through the transporter prevents nerve damage caused by excessive amounts of glutamate. "Increasing the glutamate transporter expression and removing the excess glutamate is essentially like turning on a fan to clear a smoke-filled room," says Dr. Rothstein.

As part of the Drug Screening Consortium, Dr. Rothstein found that 15 drugs from the penicillin family, named beta lactams, increased glutamate transport in cultures of spinal cord slices and therefore increased removal of this excitatory neurotransmitter.  Because this class of antibiotics can increase removal of excess glutamate, researchers hypothesized this could lead to better drug treatment therapies for neurodegenerative disorders like ALS.

"We're very excited by these drugs' abilities," says Dr. Rothstein.  "These studies show for the first time that drugs, not just genetic engineering, can increase the numbers of specific transporters in brain cells.  Because we study ALS, we tested the drugs in a mouse model of that disease, but this approach could be valuable to other conditions.  It has potential applications in numerous neurologic and psychiatric conditions that arise from abnormal control of glutamate." 

As a result of these recent findings, the NINDS will fund a multi-center clinical trial in ALS patients that is slated to start in spring 2005.  The placebo-controlled clinical trial will determine the safety and efficacy of long-term ceftriaxone treatment in patients with ALS.  "The discovery of new uses for antibiotics in ALS validates the drug screening approach as a rapid and effective method of finding new uses for existing drugs," says Jill Heemskerk, Ph.D., NINDS' program director for the screening program. "There are currently no effective drugs for these diseases, and the study of compounds identified by this approach will provide desperately needed inroads into this uncharted territory," added Dr. Heemskerk.

ALS and other neurodegenerative diseases are currently poorly understood, lack successful treatments and cause progressive disability in affected patients.  Dr. Rothstein and others in the field believe that having the ability to selectively target the glutamate transporter will be a powerful tool not only for treating neurodegenerative diseases but also for developing an important new class of drugs.  Since long-term antibiotic treatment could lead to antibiotic resistance or toxic side-effects, researchers are working to develop novel, less toxic drugs that are more selective in removing excess levels of glutamate.  Future research will also test other beta-lactam antibiotics that may be more effective.  If successful, these drugs will shed new light on treatments for neurodegenerative disorders and help to prevent nerve damage and death in patients.

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.

References: 

*Rothstein JD, Patel S, Regan MR, Haenggel C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Vang Toan S, Bruijn LI, Su Z-Z, Gupta P, Fisher PB.  "b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression."  Nature, January 6, 2005, Vol. 433, pp.73-77.

**Miller TM, Cleveland DW.  "Treating neurodegenerative disease with antibiotics."  Science, January 21, 2005, Vol. 307, pp. 361-362.

By Michelle D. Jones-London, Ph.D.

Date Last Modified: Wednesday, March 09, 2005

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