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Experimental Drug Restores Communication Between Synapses in Mouse Alzheimer's Disease Model

By BiotechDaily International staff writers
Posted on 02 Jul 2013
Image: Photomicrograph of nerve cell during an electrical recording (left), fluorescently labeled nerve cell (right), (Photo courtesy of Sanford-Burnham Medical Research Institute).
Image: Photomicrograph of nerve cell during an electrical recording (left), fluorescently labeled nerve cell (right), (Photo courtesy of Sanford-Burnham Medical Research Institute).
A new drug assembled from two [US] Food and Drugs Administration (FDA)-approved compounds completely restored amyloid-beta-induced synaptic loss in an animal model of Alzheimer's disease (AD), providing hope for rapid development of a drug that would benefit patients already displaying symptoms of the disease.

While the breakdown of communications between synapses characterizes cognitive decline in AD, the mechanism of synaptic damage remains incompletely understood.

Investigators at Sanford-Burnham Medical Research Institute (La Jolla, CA, USA) recently described a pathway for synaptic damage whereby amyloid-beta1–42 peptide (A-beta1–42) released, via stimulation of alpha7 nicotinic receptors, toxic amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA (N-methyl-D-aspartate) -type glutamate receptors (eNMDARs).

They noted that the FDA-approved drug memantine offered some limited beneficial effect in severe cases of AD. The drug belongs to the NMDA receptor antagonist class of drugs, which reduce certain types of brain activity by binding to NMDA receptors on brain cells and blocking the activity of the neurotransmitter glutamate. At normal levels, glutamate aids in memory and learning, but if levels are too high, glutamate appears to over stimulate nerve cells, killing them through excitotoxicity.

Memantine has been associated with a moderate decrease in clinical deterioration with only a small positive effect on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe Alzheimer's disease. There does not appear to be any benefit in mild disease.

The investigators reported in the June 17, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that when memantine was modified by the addition of a fragment of the FDA-approved drug nitroglycerine, the new drug—NitroMemantine—restored lost synapses in an AD animal model. The memantine component of the drug directed it to synapses where the nitroglycerine fragment inhibited glutamate release.

“We show in this paper that memantine’s ability to protect synapses is limited,” said senior author Dr. Stuart A. Lipton, professor of neuroscience, aging, and stem cell research at Sanford-Burnham Medical Research Institute, “but NitroMemantine brings the number of synapses all the way back to normal within a few months of treatment in mouse models of Alzheimer’s disease. In fact, the new drug really starts to work within hours.”

“These findings actually mean that you might be able to intercede not only early but also a bit later,” said Dr. Lipton, “and that means that an Alzheimer’s patient may be able to have synaptic connections restored even with plaques and tangles already in his or her brain. I am now optimistic that NitroMemantine will be effective as we advance to human trials, bringing new hope to both early and later-stage Alzheimer’s patients.”

Related Links:
Sanford-Burnham Medical Research Institute



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