Drugs Discovered That May Slow Progression of Lou Gehrig’s Disease
Small Molecule Drugs Turn on Protective Gene
BALTIMORE, MD -- 01/05/2005 -- A family of existing antibiotics may help prevent nerve damage and death in neurological injury including amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), according to a report in the January 6, 2005, issue of Nature. The findings may be applicable to a wide variety of neurodegenerative diseases as well as to other neurological diseases including epilepsy, peripheral neuropathy, and disorders of learning and memory.
The authors 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 authors 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, Inc. The work described in the Nature article is being extended in part under a sponsored research agreement by Ruxton Pharmaceuticals, Inc., with Johns Hopkins.
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 ALS, Parkinson’s, and multiple sclerosis. Making more transporter molecules, however, seems to counter that.
More than a dozen beta-lactam antibiotics were among protective agents identified by a National Institutes of Health-funded project to screen 1,040 Food and Drug Administration-approved drugs and nutritionals for new uses. “Ceftriaxone was neuroprotective in vitro when used in paradigms of ischemic injury [stroke] and motor neuron degeneration, both based in part on glutamate toxicity,” writes principal author Jeffrey D. Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins and Professor of Neurology and Neuroscience at Johns Hopkins. Dr. Rothstein is the scientific founder of Ruxton Pharmaceuticals and is a paid consultant to the company.
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 got no drug. Normal rats and mice that received daily ceftriaxone for up to a week had triple the usual amount of the transporter in cells, an effect that lasted some three months after treatment.
“Overall, these studies document a new property of a very common antibiotic and demonstrate that beta-lactams can activate the gene for a neurotransmitter transporter,” the researchers write in Nature.
“Although these drugs were tested in a mouse model of ALS, this discovery is much bigger than ALS,” said David S. Block, M.D., 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. The ALS mice were provided by Project ALS.
Founded in 2004, Ruxton Pharmaceuticals is an emerging pharmaceutical company that has been formed to discover, develop and market drugs for the treatment of neurodegenerative and other neurological diseases. Ruxton is focused on important indications with serious unmet medical needs such as ALS or “Lou Gehrig’s” disease.
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