1800 244 735

Helpline (02) 9874 9777

Memantine in HD: dose is everything

A drug used to treat the symptoms of Alzheimer’s disease might be beneficial in HD through altering the balance of good and bad messages coming into neurons. New research in HD mice suggests that low doses of memantine might be best, and hopefully a planned trial of low-dose memantine in HD patients will give us the answer.

What is memantine?

A drug approved for relief of Alzheimer’s Disease symptoms has been shown to be effective in mouse models of HD. The drug, called Memantine, works by blocking specific channels in neurons (brain cells). Neurons speak to each other by releasing short bursts of chemicals called neurotransmitters. Neurons communicate through the opening and closing of channels on their surfaces, in response to these neurotransmitters. The channels blocked by memantine are called ‘N-Methyl-D-Aspartate’ or NMDA receptors.

Are NMDA channels involved in HD?

It’s been suggested that too much chemical talk between neurons through these channels might be a problem in the HD brain. Neurons might literally be overexcited by incoming chemical messages, which could lead to long-term misfiring and even death of these irreplaceable cells.

It turns out that there are two distinct groups of these critical channels. One group is dedicated to passing chemical messages and is crucial for the brain to function – we’ll call them ‘good’ channels. Another group of channels, which are physically separate from the good guys, signal for ‘too much excitation’. When these ‘bad’ channels are stimulated, cell malfunctioning or death results. Of course, good and bad are relative, and likely these receptors are there for a reason.

Can we alter the functioning of NMDA channels?

Lynn Raymond and Austin Milnerwood have found that traffic through the good NMDA channels, linked to neuronal communication, was normal in HD mice. But when they looked at the activity in the bad NMDA channels, they found more in HD mouse brains than normal mouse brains. This supports the idea that chemical miscommunication is happening in HD brains, and that if we could correct it, we might have an impact on the disease. They finished their study by showing that memantine, which blocks these channels, caused HD mice to show some improvement.

But how does this work? Humans treated with drugs that completely block all NMDA channels experience serious sife effects, so how can we treat mice for HD without causing these problems?

A little goes a long way

A group of HD researchers including Mahmoud Pouladi, Shu-ichi Okamoto, Michael Hayden and Stuart Lipton might have solved part of this problem in mice. They have used memantine to show that a delicate balance is at the heart of the protection observed in HD mice.

Higher doses of the drug block both the good and bad NMDA channels because the whole brain is saturated with drug. This higher dose actually made the HD mice worse, probably because of the suppression of the good NMDA channels.

At low doses, though, memantine blocked only the bad class of NMDA channels, because they are physically easier for the drug to get to. This made the HD mice better – their brains shrank less and they performed better on some movement tests. This suggests that if we could be selective in which of these channels we block, we might have a beneficial effect in human HD brains.

Mouse studies like this should always be treated with caution. The mice used in all these the studies were treated with memantine from a very young age, and we don’t know what would happen if the mice received it only after they got sick – which is how most human patients are treated. It’s also difficult to translate doses from mice into humans.

What about human patients?

Some HD patients are already taking memantine, with or without the support of their physicians. These mouse studies highlight how careful we have to be with drugs for HD. The worst-case scenario is not that they don’t work, but that they actually make things worse.

A trial of low-dose memantine in HD patients is currently being planned, so we should soon know whether it’s safe to take, and whether it lives up to its promises in mice.

Share on facebook
Share on twitter
Share on pinterest
Share on email

Latest Research Articles

Huntington Study Group (HSG) 2020 Annual Conference: HD in Focus – Day 1

Published date: 30 October, 2020

The Huntington Study Group (HSG) is a clinical research network focused exclusively on HD. Yesterday the HSG annual conference began with a schedule jam-packed with virtual talks from researchers, clinicians and different companies who are all working towards finding new medicines for HD. The day encompassed many interesting presentations which covered a lot of the ... Read more Huntington Study Group (HSG) 2020 Annual Conference: HD in Focus – Day 1

Treatment for neurological disorder could be repurposed for Huntington’s disease patients

Published date: 22 October, 2020

While developing a drug called branaplam for patients with SMA, the pharmaceutical company Novartis discovered that it could hold promise for people with HD. The FDA has granted a special status called Orphan Drug Designation to branaplam. An existing drug…for huntingtin lowering? The pharmaceutical company Novartis has announced that the U.S. Food and Drug Administration ... Read more Treatment for neurological disorder could be repurposed for Huntington’s disease patients

Updates from the EHDN Plenary Meeting 2020

Published date: 9 October, 2020

In September, the European Huntington’s Disease Network (EHDN) hosted a virtual webinar event which comprised presentations on some of the latest scientific research as well as clinical studies of Huntington’s disease (HD). Researchers, doctors, patients and other interested folks, tuned in for an afternoon of talks as well as question and answer sessions to learn ... Read more Updates from the EHDN Plenary Meeting 2020

Sad news from the SIGNAL study: pepinemab does not influence HD symptoms

Published date: 23 September, 2020

The SIGNAL clinical trial was designed to test a drug called pepinemab in people with early Huntington’s disease. The key results of that trial were recently announced, and unfortunately, pepinemab did not slow or improve HD symptoms as hoped. What was the SIGNAL trial, and who participated? The SIGNAL trial was launched in 2015 by ... Read more Sad news from the SIGNAL study: pepinemab does not influence HD symptoms

When genes are unstable: targeting somatic instability in HD

Published date: 8 September, 2020

What is somatic instability? We tend to think of DNA as a fixed blueprint, an overarching plan for the biological bricks and bridges that constitute our cells, organs, and bodies. But like any good plan, DNA is actually dynamic and adaptable. It gets frequent use as a template for creating the RNA messages that pave ... Read more When genes are unstable: targeting somatic instability in HD

Working as a team: Changes in brain development mean some brain regions may be slacking off

Published date: 17 August, 2020

The effect of the HD genetic expansion on brain development has been a hot topic in HD research. A team of researchers led by Dr. Sandrine Humbert at the Grenoble Institut Neurosciences, examined human fetal tissue to show that the mutant HD gene causes very early changes in the patterns of early brain development. But ... Read more Working as a team: Changes in brain development mean some brain regions may be slacking off

Welcome to our new website!

Please bear with us while we iron out the last minute wrinkles! If you have any feedback about our new site, please fill out the form below.