Amid concerns about excessive prescription and resistance, antibiotics might be able finally to look forward to some good press again, because a new study in Nature (6 January) suggests that certain of these compounds may confer protection against a variety of neurological disorders.

Excessive levels of the neurotransmitter glutamate, typically resulting from defects in transport, have been linked to such neurological disorders as epilepsy and amyotrophic lateral sclerosis (ALS). However, even though the pathology of glutamate transporter dysfunction is relatively well understood, an effective therapeutic strategy has yet to emerge. “Glutamate excess is well known to cause injury,” explains Jeffrey Rothstein, a researcher at Johns Hopkins Medical Institute (Baltimore, MD). “But offsetting that by increasing transporters is a theoretical approach, not necessarily a proven approach. [Transgenic studies suggest that] it has potential, but ... we knew that if we were going to hope to use this as a neuroprotective approach, we had to have drugs that could do this.”

Thus, Rothstein and his colleagues set out to identify new neuroprotective agents. Starting with an NIH-generated library of 1,040 FDA-approved pharmaceutical and nutritional compounds, they treated sections of rat spinal cord and attempted to identify treatments that led to increased expression of the glutamate transporter gene, GLT1. Much to his group's surprise, among the top compounds found to increase GLT1 expression were 15 members of a family of widely used antibiotics, the β-lactams, which include such compounds as penicillin and amoxicillin.

This observation represents the first association of these compounds with neuroprotective properties, and Rothstein admits that, initially, “we all thought this was some error!” But repeated studies confirmed that the β-lactam antibiotics were triggering a significant increase in GLT1 transcription, with an attendant increase in actual glutamate uptake for treated spinal cord sections. To test these compounds in vivo, Rothstein and his colleagues worked with a transgenic mouse model for ALS. They treated the mice with ceftriaxone at the onset of disease symptoms and observed a marked delay in the loss of muscle strength and body weight relative to untreated controls. Drug treatment also extended the life span of the mice and reduced the extent of motor neuron loss.

Encouraged by these findings, investigators in the Rothstein lab are now trying to determine the direct targets of β-lactam action. At the same time, he adds, “if this class of drugs working on glutamate transporters is a valid therapeutic [approach], then you really don't want to be using antibiotics,” and his team is currently looking for nonantibiotic β-lactam compounds with similar neuroprotective properties.