August 24, 2010 — The adamantine derivative, memantine, preferentially blocks excessive extrasynaptic activity of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors (NMDAR), while largely sparing normal synaptic NMDAR activity, researchers report in the August 18 issue of the Journal of Neuroscience.

This observation helps explain memantine's excellent clinical safety profile in patients with Alzheimer's disease, Stuart A. Lipton, MD, PhD, and colleagues from the Del E. Webb Center for Neuroscience, Aging and Stem Cell Research at Sanford-Burnham Medical Research Institute in La Jolla, California, say.

"We have learned that it is the localization of where the drug works that is critical," Dr. Lipton told Medscape Medical News. "That's really important for developing new drugs, because we know now what receptors to aim for.

"This study elegantly demonstrates how memantine is able to protect neurons without causing harmful side effects," said Giles E. Hardingham, BSc, PhD, professor of molecular neurobiology, University of Edinburgh in the United Kingdom, who was not involved in the study.

"Memantine only blocks NMDA receptors when they are engaged in harmful activities away from the synapse; it does not interfere with the normal functioning of the NMDA receptor at the synapse," Dr. Hardingham explained.

"By discriminating between the harmful and the helpful actions of the NMDA receptor, memantine is very well tolerated in humans, and by understanding how it works, Professor Lipton's work points to how further therapies may be developed."

Preferentially Targets Extrasynaptic Channels

Excessive activation of NMDARs causes impaired function and death to nerve cells. This can contribute to many neurologic diseases, including stroke and traumatic brain injury, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and HIV-associated dementia.

However, because normal physiological NMDAR activity is important for normal brain function, blocking excessive NMDAR activity must be achieved without interfering with normal physiologic function, Dr. Lipton explained.

Dr. Lipton's team previously showed that memantine preferentially blocks neurotoxicity mediated by excessive NMDAR activity, while relatively sparing normal neurotransmission. But exactly how the drug accomplishes this was unclear, until now.

In cultured rat hippocampal autaptic neurons, memantine added at therapeutic concentrations blocked extrasynaptic but not synaptic currents mediated by NMDARs in the same neuron, the investigators report.

This, Dr. Lipton said, shows that "synaptic NMDAR activity, by and large, is left unabated by memantine, which is really fascinating. Memantine preferentially targets another set of nerve channels outside of the synapse, and it's these extrasynaptic receptors that are largely responsible for neuronal damage."

Dr. Lipton said his team is working on "an improved version of memantine called nitro-memantine that also works in this way." Several papers, Dr. Lipton said, are forthcoming on this drug.

The study was supported by grants from the National Institutes of Health and the American Heart Association. Dr. Lipton is an inventor on worldwide patents for memantine for neurodegenerative diseases. In the United States, memantine (Namenda) is licensed to Forest Pharmaceuticals Inc in New York City. Dr. Hardingham has disclosed no relevant financial relationships.

J Neurosci. 2010;30:11246-11250. Published online August 18, 2010.