glutamate

28 August 2017

Glutamate Levels Higher in People with Migraine

James Discoveries & Stats, Information 1

Glutamate is a neurotransmitter that everyone needs, but its link with migraine has become well-known. It’s not surprising that there’s a connect – glutamate transmits pain signals in the body. And now we have more evidence that glutamate levels in the brain are higher in people with migraine.

Brain Glutamate has been a big topic in the world of migraine genetics, because genetic variants related to migraine may lead to a build-up of glutamate in nerve cell junctions in the brain. Many treatmente available or being developed for migraine today may affect glutamate messages in the body. This would include treatments focused on calcium channels (such as Verapamil) and the new CGRP inhibitors.

Glutamate may be a culprit in a number of disorders other than migraine – including Alzheimer’s, multiple sclerosis (MS), and autism.

It may seem obvious that a pain transmitter would be higher when someone has a severe headache. But this study says something a little different.

Published in July in the neurological journal Brain, researches discovered that glutamate levels were higher in the brains of people with migraine – specifically in the visual cortex. Surprisingly, that was specifically in migraineurs without aura.

But the most interesting fact of all was that these were interictal levels. In other words, the glutamate was higher in migraineurs than in the general population in between attacks – when no headache was present.

Could this be related to the higher “excitability” of the migraine brain, and why we’re more prone to headaches? The researchers think so.

To read more about the study, see the abstract here: Cortical glutamate in migraine

A lot of research is being done to see how various treatments, exercise, and even diet could improve glutamate levels. But the answer is not simple, because glutamate levels are a part of a complex web of activity in the brain. But studies like this are giving us a better understanding of migraine, and giving us more evidence that glutamate plays a key role.

4 September 2010

Found: Genetic Link to "Basic" Migraine

James Discoveries & Stats, News 0

A study of genetic data from over 50,000 people has revealed a genetic link to migraine, and is providing new information about the source of migraine and its treatment.

First of all, why are we even looking for genetic links? Well, for some time now we’ve had a reasonably good theory that migraine is genetically-based. Just a good guess? No, research up to this point has given us good reason to suspect that genetics play a large role in migraine.

Genetics and Migraine: Why we know so little

Now genetic research is still relatively young. We have a lot to learn. So it will take time to learn how various genetic factors impact our health.

However, with migraine we got a head start. Certain types of migraine have a strong relation to family ties, and have a strong genetic factor. So these have been studied an unusual amount (read: familial hemiplegic migraine). And as we’ve learnt how these genetic links work, we’ve come to believe that there are strong genetic links to other types of migraine as well. And, in fact, we’ve found that many migraineurs have certain genetic abnormalities.

Dr. Sheena K. Aurora of the Swedish Headache Center in Seattle, USA, summarized some of the past research well in the book Menstrual Migraine:

There is an increasing body of evidence for the concept of central neuronal hyperexcitability as a pivotal physiological disturbance predisposing to migraine (Welch et al., 1990). The reasons for increased neuronal excitability are likely multifactoral, with an underlying genetic basis. Genetic studies have revealed an abnormality of calcium channels that has been introduced as a potential mechanism of interictal neuronal excitability (Ophoff et al., 1996)…

In other words, this is at least one way that a genetic factor seems to make the migraine brain different – more excitable.

The 2010 Migraine Genetics Study

The recently published study came from the International Headache Genetics Consortium, a cooperation of researchers from around the world. The genetic profiles of thousands of people, both migraineurs, and non-migraineurs, were studied. The chair of the consortium, Dr Aarno Palotie, says,"This is the first time we have been able to peer into the genomes of many thousands of people and find genetic clues to understand common migraine. Studies of this kind are possible only through large-scale international collaboration — bringing together the wealth of data with the right expertise and resources — so that we could pick out this genetic variant. This discovery opens new doors to understand common human diseases."

And the results?

Patients with a DNA variant on Chromosome 8 between two genes (PGCP and MTDH/AEG-1) have a significantly greater risk of developing migraine. Why? The link appears to relate to something called glutamate.

Glutamate is a common neurotransmitter – it transmits messages in the body. In fact, it transmits pain signals. This particular DNA variant regulates glutamate levels. Is build-up of glutamate causing problems? If so, could we create a targeted treatment to prevent it?

Actually, glutamate has already been the target of research into migraine treatment. Take for example Tezampanel, and ADX10059. Namenda (memantine) is an example of a treatment already being used for migraine, which deals with glutamate.

There is still a long way to go in these studies. For one thing, it’s likely that more genetic factors will be found relating to migraine. Also, even this link needs more study. How common is it? Does it really lie at the heart of migraine in general, or only more severe versions? What about various types of chronic headache?

However, this is more evidence that we’ve come a long way in migraine research, and are getting a much better picture of what’s really going on in the body of a migraineur.

More on this study: First Genetic Link to Common Migraine Exposed

30 March 2009

ADX10059 – another Migraine Drug in the Pipeline

James Discoveries & Stats, Medications 3

A couple of weeks ago I mysteriously referred to a drug called ADX10059, but didn’t say much about it. So let’s take a quick look at another new migraine drug that is currently in the testing phase.

As I mentioned in the post The Latest on Tezampanel, a new Migraine Drug, ADX10059 also has to do with glutamate. You can read the previous post for more on the connection between glutamate and migraine, as well as various types of chronic pain.

The technical description of ADX10059: a metabotropic glutamate receptor 5 negative allosteric modulator. Wow! We won’t go into every detail of how it functions, except to say that it inhibits glutamate, though in a different way than Tezampanel.

Testing is still in the second phase. At the very least, the results so far show that ADX10059 is getting rid of migraine pain in some people, so there’s reason to continue with the testing.

As with Tezampanel, it is hoped that this drug will break into the migraine chain-reaction and "interrupt the migraine circuit". Keep an eye on these emerging drugs – they’re different than what has come before, and are opening up a new field of study for migraine and other types of chronic pain.

ADDEX Pharmaceuticals is testing ADX10059, and has a brief explanation of mGluR5 & migraine on their site. Expect to hear more about ADX10059 next year (2010).

12 March 2009

The Latest on Tezampanel, a new Migraine Drug

James Discoveries & Stats, Medications 9

Trials for the new migraine drug, Tezampanel (NGX424), are moving quickly ahead. So it’s time to catch up on what this drug is, and who it might help.

Tezampanel is based on an emerging understanding of the role of glutamate (an amino acid) in pain. Targeting glutamate receptors (either through antagonists like Tezampanel or through modulators like ADX10059) is a new concept that may help not only those with migraine, but also muscle spasticity, fibromyalgia, arthritis, diabetic neuropathy, epilepsy, and neuropathic pain in general. It may also suppress symptoms of opioid medication withdrawal.

Why target Glutamate?

Glutamate is a key neurotransmitter. It’s called an excitatory neurotransmitter, and is the one most commonly found in your body.

Glutamate has a number of functions in your body, which may include to ability to learn and memorize, and the transmission of pain signals.

During certain stages of the pain chain-reaction, glutamate gets very busy sending signals. In certain people with chronic pain especially, there may be too much glutamate, inducing more pain than should be necessary.

Researchers are actually getting very excited about levels of glutamate, because this may be the key to understanding the mysterious chronic pain in many people. Could it be that some people’s chronic pain could be "seen" by the levels of glutamate? Better yet, could the pain chain reaction be stopped or slowed by controlling glutamate?

Glutamate does have a role in migraine. It’s present in the trigeminal nerve (where migraine pain often radiates from). It plays a role in cortical spreading depression (a brain "storm" that is a major part of a migraine attack), and seems to be key in causing central sensitization, where certain neurons in the spinal cord become sensitized, possibly causing increasing chronic pain. (more about what happens during a migraine attack)

Enter Tezampanel

Tezampanel (also called NGX424) is a drug being developed by TorreyPines Therapeutics, based on research done at Johns Hopkins University. It’s unlike any other drug in what it does. In scientific terms, Tezampanel is an ionotropic glutamate receptor antagonist that targets the AMPA and kainate sub-type receptors. Glutamate receptors receive glutamate and become activated – this drug is designed to interrupt the process.

There are actually two drugs here being tested, but we’ll get to the second in a moment. Tezampanel itself is injected, and was compared with injections of Imitrex (sumatriptan). It was found to work as well as Imitrex. Symptoms that Tezampanel seems to help with:

pain (and excessive pain sensitivity)
nausea
sensitivity to light and sound
allodynia (sensitive/painful areas on the skin)

Tezampanel and NGX426

Another related drug in an earlier stage of testing is NGX426. This is a "prodrug" of Tezampanel, which means that it causes Tezampanel to be formed in the body.

NGX426 is an oral drug, not an injection. Last month (February 2009) a Phase I trial was completed, and so far so good (read the results of the this early trial). NGX426 seems to have promise for relieving pain in migraine.

Side effects?

When a new drug comes out, there is always hope that many patients suffering from the side effects of something else may be able to make the switch. How is Tezampanel looking regarding side effects?

So far the side effects seem to be fairly minimal. Common ones seem to be:

pain at the injection site (of course this wouldn’t happen if you took NGX426 orally)
dry mouth
some other side effects in very few people may include dizziness and sleepiness

The next step

Tezampanel is heading into the last stages of testing. NGX426 is farther behind, just heading into Phase II (of III). TorreyPines Therapeutics is just putting together the funding it needs to carry out the next step.

Summary

Drugs coming out that are totally different than what has come before are especially interesting. Not only may they help people who haven’t been helped, they may also lead to new treatments and breakthroughs. When it comes to chronic pain, Tezampanel is one to watch.

From what we’ve seen so far, this drug may work well for some people who have been unable to take other types of migraine drugs due to side effects or other medical conditions. It may also hold hope for those who have chronic pain conditions, including chronic migraine.

TorreyPines has more on Tezampanel and NGX426 here

Heads up from Ellen Schnakenberg