The researchers demonstrated that ceftriaxone, a beta-lactam antibiotic, turns on a gene that encodes for the glutamate transporter GLT-1. As a result, more glutamate transporter protein is present and functioning in the brain; the researchers showed this to be protective against brain cell degeneration.
The newfound ability of ceftriaxone, other beta-lactam antibiotics, and other classes of drugs to activate glutamate transporters and to protect nerves, and the drugs’ potential therapeutic use in a wide range of neurological and psychiatric conditions, are covered by patent applications held by The Johns Hopkins University and licensed to Ruxton Pharmaceuticals.
Glutamate is the most abundant neurotransmitter in the brain. Glutamate transporters clear the neuronal synapses of excess glutamate similar to the way an air vent circulates and clears the air in a room. Too much glutamate resulting from too few glutamate transporters, as is observed in neurodegenerative diseases, overexcites nerve cells and harms them, a process called glutamate excitotoxicity.
Excess synaptic glutamate has long been known as a source of nerve damage in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), Parkinson’s, and multiple sclerosis. Making more transporter molecules, however, seems to counter that.
People with ALS normally experience progressive weakness, paralysis, and death within three to five years of diagnosis. In mouse models of ALS, daily injections of ceftriaxone given after symptoms have developed delayed both nerve damage and the outward signs of the disease. Mice on ceftriaxone also lived significantly longer than those who received no drug.
“Although these drugs were tested in a mouse model of ALS, this discovery is much bigger than ALS,” said Dr David Block, president and CEO of Ruxton Pharmaceuticals.
“This approach has potential applications in numerous neurologic and psychiatric conditions that arise from abnormal control of glutamate. In diseases such as ALS, we hope that this approach might eventually deliver drugs that can be used in combination with other approaches, similar to combinations used in HIV and oncology.”
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.