Featured Research

from universities, journals, and other organizations

New drug reverses loss of brain connections in Alzheimer's

Date:
June 17, 2013
Source:
Sanford-Burnham Medical Research Institute
Summary:
The first experimental drug to boost brain synapses lost in Alzheimer's disease has been developed by researchers. 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.

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 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 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 (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.

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 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 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 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.


Story Source:

The above story is based on materials provided by Sanford-Burnham Medical Research Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Maria Talantova, Sara Sanz-Blasco, Xiaofei Zhang, Peng Xia, Mohd Waseem Akhtar, Shu-ichi Okamoto, Gustavo Dziewczapolski, Tomohiro Nakamura, Gang Cao, Alexander E. Pratt, Yeon-Joo Kang, Shichun Tu, Elena Molokanova, Scott R. McKercher, Samuel Andrew Hires, Hagit Sason, David G. Stouffer, Matthew W. Buczynski, James P. Solomon, Sarah Michael, Evan T. Powers, Jeffery W. Kelly, Amanda Roberts, Gary Tong, Traci Fang-Newmeyer, James Parker, Emily A. Holland, Dongxian Zhang, Nobuki Nakanishi, H.-S. Vincent Chen, Herman Wolosker, Yuqiang Wang, Loren H. Parsons, Rajesh Ambasudhan, Eliezer Masliah, Stephen F. Heinemann, Juan C. Piña-Crespo, and Stuart A. Lipton. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. PNAS, June 17, 2013 DOI: 10.1073/pnas.1306832110

Cite This Page:

Sanford-Burnham Medical Research Institute. "New drug reverses loss of brain connections in Alzheimer's." ScienceDaily. ScienceDaily, 17 June 2013. <www.sciencedaily.com/releases/2013/06/130617160849.htm>.
Sanford-Burnham Medical Research Institute. (2013, June 17). New drug reverses loss of brain connections in Alzheimer's. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2013/06/130617160849.htm
Sanford-Burnham Medical Research Institute. "New drug reverses loss of brain connections in Alzheimer's." ScienceDaily. www.sciencedaily.com/releases/2013/06/130617160849.htm (accessed September 1, 2014).

Share This




More Mind & Brain News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Coffee Then Napping: The (New) Key To Alertness

Coffee Then Napping: The (New) Key To Alertness

Newsy (Aug. 30, 2014) — Researchers say having a cup of coffee then taking a nap is more effective than a nap or coffee alone. Video provided by Newsy
Powered by NewsLook.com
Young Entrepreneurs Get $100,000, If They Quit School

Young Entrepreneurs Get $100,000, If They Quit School

AFP (Aug. 29, 2014) — Twenty college-age students are getting 100,000 dollars from a Silicon Valley leader and a chance to live in San Francisco in order to work on the start-up project of their dreams, but they have to quit school first. Duration: 02:20 Video provided by AFP
Powered by NewsLook.com
Baby Babbling Might Lead To Faster Language Development

Baby Babbling Might Lead To Faster Language Development

Newsy (Aug. 29, 2014) — A new study suggests babies develop language skills more quickly if their parents imitate the babies' sounds and expressions and talk to them often. Video provided by Newsy
Powered by NewsLook.com
Electrical Stimulation Boosts Brain Function, Study Says

Electrical Stimulation Boosts Brain Function, Study Says

Newsy (Aug. 29, 2014) — Researchers found an improvement in memory and learning function in subjects who received electric pulses to their brains. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins