Sanford-Burnham scientists uncover new clues to the molecular action of memantine, a drug used to treat Alzheimer's disease, that show why side effects are rare.
Alzheimer's disease destroys brain cells and their connections (called synapses), causing memory loss and other cognitive problems that disrupt work, hobbies and daily life. Symptoms can be alleviated, in part, by the drug memantine (marketed in the United States as Namenda), which is currently FDA-approved to treat moderate-to-severe Alzheimer's disease and was, in part, developed by Stuart A. Lipton, M.D., Ph.D., Director of the Del E. Web Center for Neuroscience, Aging and Stem Cell Research at Sanford-Burnham Medical Research Institute (Sanford-Burnham). Memantine improves symptoms by blocking abnormal activity of glutamate, a chemical that transmits messages between nerve cells. In a study appearing August 18 in The Journal of Neuroscience, a team of investigators at Sanford-Burnham led by Dr. Lipton unravel exactly how memantine helps Alzheimer's patients without causing serious side effects.
"While memantine is partially effective in treating Alzheimer's disease, one of its major advantages is how safe and well-tolerated it is clinically," said Dr. Lipton
In treating any disease, one of the most difficult parts of designing a new drug is finding ways to maximize its beneficial effect while minimizing harmful side effects. Memantine is a particularly safe treatment for Alzheimer's disease because it dampens excessive glutamate signaling that occurs away from synapses without blocking glutamate activity at the synapses. This is important because interfering with synaptic glutamate signaling would disrupt normal brain activity.
"We showed definitively for the first time that memantine, the drug our group developed for Alzheimer's disease, works in a unique way," Dr. Lipton said. "It inhibits a protein that binds glutamate called the NMDA receptor, but predominantly blocks NMDA receptors that signal molecularly to cause neuronal injury and death. It spares the synaptic receptors that mediate normal communication between nerve cells in the brain."
This finding helps explain why the drug is so well tolerated by Alzheimer's patients and might provide hints for the development of future therapies targeting the NMDA receptor and similar cellular machinery in other diseases.
As many as 5.3 million Americans are living with Alzheimer's, currently the seventh-leading cause of death in the United States.
This study was supported by grants from the National Institute for Neurological Diseases and Stroke (NINDS), the National Eye Institute (NEI) and the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), all parts of the National Institutes of Health (NIH), and the American Heart Association (AHA). Memantine (Namenda®) is licensed and marketed by Forest Pharmaceuticals, Inc. in New York City. For more information about Sanford-Burnham research, visit beaker.sanfordburnham.org.
Original paper: Xia P, Chen HSV, Zhang D, Lipton SA. Memantine preferentially blocks extra-synaptic over synaptic NMDA receptor currents in hippocampal autapses. The Journal of Neuroscience. Published online August 18, 2010.
About Sanford-Burnham Medical Research Institute - Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 - 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.
Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neuro-degeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org
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