Reversing the loss of brain connections in Alzheimer’s disease

By Bruce Lieberman
June 17, 2013
59

The first experimental drug to boost brain synapses lost in Alzheimer’s disease has been developed by researchers at Sanford-Burnham. 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 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 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.

Talantova, M., Sanz-Blasco, S., Zhang, X., Xia, P., Akhtar, M., Okamoto, S., Dziewczapolski, G., Nakamura, T., Cao, G., Pratt, A., Kang, Y., Tu, S., Molokanova, E., McKercher, S., Hires, S., Sason, H., Stouffer, D., Buczynski, M., Solomon, J., Michael, S., Powers, E., Kelly, J., Roberts, A., Tong, G., Fang-Newmeyer, T., Parker, J., Holland, E., Zhang, D., Nakanishi, N., Chen, H., Wolosker, H., Wang, Y., Parsons, L., Ambasudhan, R., Masliah, E., Heinemann, S., Pina-Crespo, J., & Lipton, S. (2013). A  induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1306832110

ResearchBlogging.org

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59 Comments

  1. sounds really promising. As an AD caregiver, I can only hope they will rush this new medicine through the approval process rather than spending time trying to get a patent , which seems too often to be the case..

  2. This is GREAT news!!! We need something do treat/cure this horrendous disease!! Now if only the FDA would fast track this and get it out to the millions of people suffering!

  3. Patrick Bartosch
    Patrick Bartosch on

    Thanks to our Beaker readers for all your great questions and comments. This Alzheimer’s research is in the very early stages and is not yet ready for clinical trials. Sanford-Burnham conducts laboratory-based research, not involving patients. For information on clinical trials, please visit this government website: clinicaltrials.gov.

  4. Beverly Sleph on

    My husband has been taking Namenda since the day it was FDA approved — a very long time ago.
    We need the new drug NOW while it still may help.

  5. This research deals with a glutamate disturbance. Is it possible that there could be a link between the processes that initiate amyloid plaque formation in the brain and those that trigger metabolic syndrome, a frequent complication of heart disease?

  6. Is this still in the clinical trial stage or is it something we can get now? If still in clinical trial how can we become part of the trial? Thank you for your work.

    • Patrick Bartosch
      Patrick Bartosch on

      Hi Mary,

      This is not in clinical trials yet. The research was done in animal models and it may take a while until it goes into the clinic. For clinical trials, we recommend checking out clinicaltrials.gov. Also, continue reading Beaker for updates on NitroMemantine.

      Patrick

  7. Elizabeth Crouse on

    As a caregiver, this is exciting news. We could use some help and I pray this will not take long to get on the market. Thank you, Elizabeth

  8. If the dose of nitroglycerin and memantine that produced the desired effect are known, wouldn’t it be possible for a physician to prescribe each drug , since each is already approved by the FDA?

    • Patrick Bartosch
      Patrick Bartosch on

      Hi Linda,

      This is not in clinical trials yet. The research was done in animal models and it may take a while until it goes into the clinic. For clinical trials, we recommend checking out clinicaltrials.gov. Also, continue reading Beaker for updates on NitroMemantine.

      Patrick

    • Patrick Bartosch
      Patrick Bartosch on

      Hi Cathy,

      We honestly don’t know yet. Keep reading Beaker for updates on NitroMemantine.

      Patrick

  9. Gary Johnston on

    I am very excited about the prospects of NitroMemantine and it’s future trials. We would be interested in further information and possible involvement in such trials. Further, We would consider making a donation for it’s advancement.

    • Patrick Bartosch
      Patrick Bartosch on

      Hi Gary,

      Thanks for your comment. This research was done in animal models and we do not know yet when it will move to the clinic. We’ll definitely keep everyone updated here on Beaker on our progress. If you’re interested in clinical trials, we recommend you visit clinicaltrials.gov.

      If you’d like to make a donation to Sanford-Bunrham, please visit our website: http://www.sanfordburnham.org/oursupporters/Pages/OurSupporters.aspx.

      Thank you!

      Patrick

  10. At last some encouraging news re. Alzheimer’s. When do you except NitroMemantine to be available or is there anyway to preceed that date? How can we find out about the human trails? Thank you.

    • Patrick Bartosch
      Patrick Bartosch on

      Hi Carol,

      This is in the very early stages of the drug development process and we do not know the timeline for any clinical studies yet. Keep following Beaker and check out clinicaltrials.gov for new information.

      Thanks,

      Patrick

    • Patrick Bartosch
      Patrick Bartosch on

      Hi,

      This is in the very early stages of the drug development process and we do not know the timeline for any clinical studies yet. Keep following Beaker and check out clinicaltrials.gov for new information.

      Thanks,

      Patrick

    • Patrick Bartosch
      Patrick Bartosch on

      Hi Ellen,

      This is in the very early stages of the drug development process and we do not know the timeline for any clinical studies yet. Keep following Beaker and check out clinicaltrials.gov for new information.

      Thanks,

      Patrick

  11. rory hammond on

    I for 1 am so happy to hear that there may be some help come to patients of this disease on the horizons. My 76 yr old mother was put in a nursing home 1 yr ago,she is highly functioning,and as these tests move to humans ,id like to feel maybe there is some hope out there for so many people

  12. Ernest Hylton on

    This is great news!! My wife has Alzheimers and I am very interested in the progress of this possible cure.

  13. Caroline Booth on

    Have read with great interest your article re New Drug Reverses Loss of Brain Connections in Alzheimers.
    My husband is 72 and has just been diagnosed with Alzheimers. Very interested in your new findings re NitroMemantine and would be interested to know when it might be available of if you need volunteers for your trials .
    FAO Stuart A Lipton M.D. Ph.D

    Ivor and Caroline Booth (Coventry)

  14. Michelle Ryan on

    This is wonderful news! I would like to be informed when and where Clinical Trials will begin hopefully in the Orlando area. My mother has suffering with this for 7 years. She is already on Namenda and Aricept.

  15. Marcelli Stefania on

    I hope that you will give us in this blog immedially informations about: were and wan could be possibile to test this cure

  16. Marcelli Stefania on

    Sorry for my Bad English, i repeat:
    I hope that you will give us in this blog immedially informations about: where and when it could be possibile to test this cure

  17. Ron Saltzman on

    The success of NitroMemantine is wonderful news.

    My wife has been diagnosed with early to mid stage alzheimers and we would greatly appreciate being advised when you will be interviewing candidates for acceptance into a clinical trial study of
    NitroMemantine. If she were accepted we would move to wherever the study was being conducted.

  18. Heloisa Carvalho e SIlva on

    I want to know how you will apply this experimental drug in human? How you choose people for the experiemntal phase? My mon have alzheimer, that’s why I’m interest.
    yours faithfully
    Heloisa

  19. crystal gwinn on

    Please let me know when clinical trials for nitromemantine will be available. My husband has moderate alzeimer’s and is willing to travel any distance in order to participate.

  20. Donna Futrell on

    I would like to get my mother on this clinical trial. She in moderate stage Alzheimer’s disease. Her neurologist does not do experimental drugs and we would like to do everything possible for our loved one. We will travel any distance to participate.

  21. Please let me know when the human clinical trial starts for the new FDA approved Nitromemanitine, my mother would really benefit form this drug trial.

    Thank you,

    Alexandria Ramage

  22. I would like all information on this drug and to get my mother on this clinical trial. She in moderate stage Alzheimer’s disease and has been for more than 5 years. She was taking Namenda, but stopped because the drug is expensive and there was no change. I am will to travel and try anything that may help get my mother (also my best friend) get some if not all of her memory back, or just stop the progression of the diease.

  23. My husband has been diagnosed with MCI. His annual checkup shows that it has become worse. Please add him to your list of possible candidates for clinical trials.

  24. Charlene Burton on

    Please let me know when human trials begin in the Houston TX area. When is Nitromemantine going to be available to the public?

  25. My father is 59 and has been diagnosed with AD about 10 years ago; he has about 3 years to live according to the neurologists.
    We already participated in experimental medication here in Belgium (but no effect) and are willing to keep trying anything that comes along. For himself or for science and the future.
    Please feel free to contact me any time!

  26. My mother is 51 with early onset. I’m her 24 year old daughter, whom takes care of her with no help. I put my life at a stand still because I felt as if she was too young to go to a nursing facility. By my mother being so young she’s yet to get retirement and disability is a long process. I have been paying utilities out of Child support and the rent has been behind. I left my full time job as a CNA to take care of her. No one else would since my family advise me to put her in a facility… It’s sad to here other stories similar to mine but Alzheimers is common in the elderly (I worked in a nursing home) but my mother is barely 50 for Christ sakes.

  27. Laurie Wright, R.N. on

    It’s interesting to note that the release of excessive amounts of glutamate is part of the mechanism of action – making me wonder if there may be some correlation or some application of this science for migraine sufferers, as often MSG or high levels of natural glutamate ingestion can trigger severe migraines for some people. I would love to hear back from the researchers regarding this.

    The article above states the synapses started being restored within hours. I would like to know if that translates into visible behavioral/cognitive changes? If so, how quickly were cognitive/behavioral improvements noted?

    Thank you so much for all the work that you do!

  28. Ingrid Williams on

    I’ve been reading the various articles and I like most of the people that have commented would like more information. My mother is 75 and has Lewy Body Dementia; she is highly functional however has frequent episodes of delusion accompanied with confusion. My father and I have tried to be as pro-active as possible when caring for her and NitroMemantine sounds like a groundbreaking new treatment but we need more info. such as the side-effects and status updates on clinical trials.

  29. Barbara Heuberger on

    This certainly gets my attention. My husband is extraordinarily healthy, but is in late mid-stage Alzheimer’s. Like many have stated, we want to participate in this trial. Is there a timeline when the trials will begin? For us, sooner is better!

  30. Please, let me know when the trial begins! My father, aged 64, is affected by Alzheimer’s disease at the several stage and we don’t have any hope to help him in Italy.
    Thanks.

  31. Why does it take such a long time for two FDA-approved medicines which = nitromemantine to reach the clinical trials submissions stage? Obviously checking clinicaltrials.gov for new information is a good idea, but could someone take a guess at a timeline.
    Many thanks and all the best . . .

  32. Margy Jennings on

    Please let me know about your upcoming trials. My husband has early stages. He is on no Rx. Take supplements and Is in very good physical health.

    • Patrick Bartosch
      Patrick Bartosch on

      Hello Margy,

      Thanks for your comment and your interest in Sanford-Burnham. We are a basic medical research institute and generally don’t work with patients. Once this compound makes it into clinical trials, you can find more information on clinicaltrials.gov.

      Best,

      The Sanford-Burnham Communications Team

  33. Nicolai Kilian on

    Hello Patrick Bartosch,

    please tell us, what is the current state in the drug development process? What are the scientists currently working on regarding NitroMemantine?

  34. Is this treatment atall availble to humans? If so i would want my Father in law to get involved. He is in India. Is there any possibilities that he can be a part of test studies? Please advise whole family is really getting emotionally drained because of his detoriating health. Is this drug still available for us to get it?

  35. Stefania Chiapello on

    My mum is in late mid-stage Alzheimer’s. As it takes time for the clinical trials and as we are talking about approved drugs, is it possible in the meanwhile to combine the two medicines under a medical supervision?
    We do not have so much time and absolutely anything to lose.

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