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Biological Chemistry

Antibiotics Protect Neurons

ß-Lactams slow neurological disease by reducing excess levels of glutamate

by Sophie L. Rovner
January 10, 2005 | A version of this story appeared in Volume 83, Issue 2

DRUG DISCOVERY

ß-Lactam antibiotics apparently have more going for them than their ability to kill bacteria. These drugs could potentially serve as the basis for treatments for neurological disorders including amyotrophic lateral sclerosis (ALS)--also known as Lou Gehrig's disease.

Researchers uncovered this additional capacity of ß-lactam antibiotics while screening 1,040 FDA-approved drugs for additional uses. Jeffrey D. Rothstein, a neurologist who heads the Robert Packard Center for ALS Research at Johns Hopkins University, and colleagues were looking for compounds that could boost production of the glutamate transporter GLT1.

Glutamate is an excitatory neurotransmitter released by neurons to pass electrical signals to other neurons. Although glutamate is necessary for proper signaling, it's not a benign messenger. If too much glutamate accumulates in the synapses between neurons, the excess neurotransmitter can overstimulate and kill off these cells, contributing to conditions such as ALS.

To stave off such damage, other neural cells known as astroglia sop up the excess glutamate. Glutamate is drawn into those cells through the transporter protein GLT1, which is embedded in the astroglial cell membrane. Once glutamate is sequestered inside the astroglia, the neurotransmitter is unable to harm neurons.

When Rothstein and his colleagues screened the FDA-approved drugs, they found that ß-lactam antibiotics and some of their derivatives produced a neuroprotective effect by tripling expression of GLT1 [Nature, 433, 73 (2005)]. In mice that served as a model for ALS, treatment with the ß-lactam ceftriaxone slowed progression of the disease.

Rothstein says his team's work demonstrates "for the first time that drugs, not just genetic engineering, can increase numbers of specific transporters in brain cells."

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