New drug reverses loss of brain connections in Alzheimer's disease

June 17, 2013
This is a photomicrograph of nerve cell during an electrical recording (left), fluorescently labeled nerve cell (right). Credit: Sanford-Burnham Medical Research Institute

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.

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 , 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 Alzheimer's 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 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 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 , Lipton and his team mapped the pathway that leads to synaptic damage in Alzheimer's. They found that amyloid beta peptides, which were once thought to injure synapses directly, actually induce the release of excessive amounts of the from called that are located adjacent to the .

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.

Explore further: Chemical reaction keeps stroke-damaged brain from repairing itself

More information: Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss,

Related Stories

Recommended for you


Adjust slider to filter visible comments by rank

Display comments: newest first

1.6 / 5 (7) Jun 17, 2013
I just love REAL science.
1.7 / 5 (6) Jun 17, 2013
Hey vd do you think this might make normal people like you even smarter??
3.4 / 5 (5) Jun 17, 2013
Normal within a few months of treatment? This is huge news if the article is reporting it correctly.

I wonder how long before the FDA will allow it to save people's lives. I would hope it's on a really fast track to approval.
1.9 / 5 (7) Jun 18, 2013
This is brilliant news for sufferers and their families.

I wonder how long before the FDA will allow it to save people's lives. I would hope it's on a really fast track to approval.

What's the bet though that the FDA will find some last minute excuse to disapprove the drug and suspend all further trials.
4 / 5 (2) Jun 18, 2013
Absolutely fantastic!! Now just to get the FDA to fast track this and get it out to the millions of patients that NEED it!!!
3 / 5 (4) Jun 18, 2013
Alas, this story has received no other notice that I can find. Not a good sign for something with such awesomely significant potential (not to mention public interest.)
3 / 5 (1) Jun 18, 2013
Can anyone clarify the structure of this compound to me? In one part they describe it as a mixture (eg of mematine plus nitroglycerin) another they describe it as a nitro group joined to is it a ring-nitro ester of mematine, or a mixture??
Thanks from a confused medicinal chemist......
3 / 5 (4) Jun 18, 2013
Would it not speed approval were it a mixture of already approved chemicals rather than a new chemical? My reading, unfortunately, leads me to believe it's a new chemical.

If the latter, could just mixing them cause the reaction?
1.6 / 5 (7) Jun 18, 2013
I couldn't agree more. If only that was how it worked. Unfortunately, it isn't. Money talks and the FDA have no desire to push these things any faster than the normal glacial speed that they travel, nor do they even follow through with them half of the time if the funds aren't there. Just look at the autism drug trial, which was the only hope that families were given - that was canceled prematurely, and the only reason they gave was because of "unforeseen circumstance" and refused to comment further. A lot of cancer trials also "fail" during the midstages. And it makes me wonder if there's more to it than the drug's effectiveness.
Open-minded Individual
5 / 5 (1) Jun 19, 2013
Too bad this new drug is already obsolete... There is a plant that can already do this, with no side-effects, but since they cant patent a plant and because it is very inexpensive there is no money to be made. Pharmaceutical companies have no interest in helping people, only making profits, this is fact.

Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

Received: 19 September 2011
Accepted: 16 January 2012
Published: 16 January 2012

Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.
Open-minded Individual
5 / 5 (1) Jun 19, 2013
...Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.

In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

Research conducted in Bethesda Maryland led to Patent 6,630,507 held by the United States of America since 2003 that teaches that the lack of psycho-activity in CBD allows doses that are 100-200 times greater than the tolerable dose of THC. The articulated "Effective oral human dosage schedule is 20 mg / kg body weight" requires a considerable amount of cannabis. The simplest approach is to consume the trichrome laden fully mature flower along with the 80-day leaf.
3 / 5 (4) Jun 19, 2013
Given that this is a compound of existing drugs and hoping that the synthesis that combines them is not too difficult I don't think that waiting for the FDA will be much of a problem. A black market will spring up immediately. If you think the rich and powerful afflicted with this are going to sit around twiddling their fingers, think again.

I really don't think one will need to be rich and powerful to obtain this in fairly short order regardless of the wishes of the FDA. You don't play by the rules when you know your brain is melting.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.