Researchers Develop Novel Drug That Reverses Loss of Brain Connections in Models of Alzheimer's

Newswise LA JOLLA, Calif., June 17, 2013 The first experimental drug to boost brain synapses lost in Alzheimers 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.

The 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, who is also a practicing clinical neurologist, shows that NitroMemantine can restore synapses, representing the connections between nerve cells (neurons) that have been lost during the progression of Alzheimers in the brain. The research findings are described in a paper published June 17 by the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The focus on a downstream target to treat Alzheimers, rather than on amyloid beta plaques and neurofibrillary tanglesapproaches which have shown little successis 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 Alzheimers patient may be able to have synaptic connections restored even with plaques and tangles already in his or her brain.

Targeting lost synapses

In their study, conducted in animal models as well as brain cells derived from human stem cells, Lipton and his team mapped the pathway that leads to synaptic damage in Alzheimers. They found that amyloid beta peptides, which were once thought to injure synapses directly, actually induce the release of excessive amounts of the neurotransmitter glutamate from brain cells called astrocytes that are located adjacent to the nerve cells.

Normal levels of glutamate promote memory and learning, but excessive levels are harmful. In patients suffering from Alzheimers 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

Liptons lab had previously discovered how a drug called memantine can be targeted to eNMDA receptors to slow the hyperactivity seen in Alzheimers. This patented work contributed to the FDA approval of memantine in 2003 for the treatment of moderate to severe Alzheimers disease. However, memantines effectiveness has been limited. The reason, the researchers found, was that memantinea positively charged moleculeis 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 nitroglycerina second FDA-approved drug commonly used to treat episodes of chest pain or angina in people with coronary heart diseasecould 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, Liptons 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 memantines 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 Alzheimers disease. In fact, the new drug really starts to work within hours.

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Researchers Develop Novel Drug That Reverses Loss of Brain Connections in Models of Alzheimer's