June 19, 2013
Drug Found That Reverses Loss of Brain Connections in Alzheimer’s Disease
|The first experimental drug to boost brain synapses lost in Alzheimer's disease has been developed by researchers at Sanford-Burnham Medical Research Institute. The drug, called NitroMemantine, combines two FDA-approved medicines to stop the destructive cascade of changes in the brain that destroys the connections between neurons, leading to memory loss and cognitive decline.|
In a decade-long study, led by Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, has demonstrated that the drug NitroMemantine can restore synapses, representing the connections between nerve cells (neurons) that have been lost during the progression of Alzheimer's in the brain.
The research findings are described in a paper published by the Proceedings of the National Academy of Sciences(PNAS).
The focus on a downstream target to treat Alzheimer's, rather than on amyloid beta plaques and neurofibrillary tangles -- approaches which have shown little success -- "is very exciting because everyone is now looking for an earlier treatment of the disease," Lipton said. "These findings actually mean that you might be able to intercede not only early but also a bit later." 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.
Normal levels of glutamate promote memory and learning, but excessive levels are harmful. In patients suffering from Alzheimer's disease, excessive glutamate activates extrasynaptic receptors, designated eNMDA receptors (NMDA stands for N-methyl-D-aspartate), which get hyperactivated and in turn lead to synaptic loss.
How NitroMemantine works
Lipton's lab had previously discovered how a drug called memantine can be targeted to eNMDA receptors to slow the hyperactivity seen in Alzheimer's. This patented work contributed to the FDA approval of memantine in 2003 for the treatment of moderate to severe Alzheimer's disease. However, memantine's effectiveness has been limited. The reason, the researchers found, was that memantine -- a positively charged molecule -- is repelled by a similar charge inside diseased neurons; therefore, memantine gets repelled from its intended eNMDA receptor target on the neuronal surface.
In their study, the researchers found that a fragment of the molecule nitroglycerin -- a second FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart disease -- could bind to another site that the Lipton group discovered on NMDA receptors. The new drug represents a novel synthesis connecting this fragment of nitroglycerin to memantine, thus representing two FDA-approved drugs connected together. Because memantine rather selectively binds to eNMDA receptors, it also functions to target nitroglycerin to the receptor. Therefore, by combining the two, Lipton's lab created a new, dual-function drug. The researchers developed 37 derivatives of the combined drug before they found one that worked, Lipton said.
By shutting down hyperactive eNMDA receptors on diseased neurons, NitroMemantine restores synapses between those neurons. "We show in this paper that memantine's ability to protect synapses is limited," Lipton said, "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."
To date, therapies that attack amyloid plaques and neurofibrillary tangles have failed. "It's quite disappointing because I see really sick patients with dementia. However, I'm 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," Lipton said.
It is unclear what the effects of NitroMemantine are on non-Alzheimer's users, or if it has the potential to be a neuro-enhancer.
SOURCE Sandford-Burnham Medical Research Institute
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Tags: Alzheimer's disease, drug discovery, medicine, memantine, NitroMemantine, Sanford-Burnham Medical Research Institute, Stuart A. Lipton
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