This Is MS Multiple Sclerosis Community: Knowledge & Support

I don't think this study has been posted here yet, but sometimes it's hard to keep up.



Breakthrough in brain injury study at University of Leicester

Drs Robert Fern and Mike Salter of the Department of Cell Physiology and Pharmocology at the University of Leicester had their findings published in the science journal Nature.

Their study is particularly important as it identifies the cause of damage to the brain and the mechanism by which this occcurs - thereby raising the possibility of drugs being developed in the future which may help to reduce injury and the disease states that follow.

Dr Fern said: "This project has taken over a year to complete and has produced some rather important findings. We believe that we may have opened a new window into how the brain becomes damaged in a number of important diseases ranging from stroke to multiple sclerosis and spinal cord injury. We will now continue to study the particular brain receptor that is involved in the hope of discovering a way to block the receptor and therefore avert brain injury for a large number of patients."

This work was supported by a grant from the National Institutes of Neurological Disorders and Stroke to R.F.


PLEASE FIND FOLLOWING AN EXPALANATORY NOTE ABOUT THE RESEARCH AT LEICESTER

The brain is the organ responsible for our thoughts, memories, sensations and emotions. All these functions occur because neurons, the "little grey cells" of Agatha Christie's Hercule Poirot, are able to pass signals between one another using a chemical called glutamate.

Glutamate is released by neuronal structures called synapses and interacts with special receptors on neighboring neurons. While most people will have heard of neurons, it is not commonly known that only about half of the brain is actually made up of these cells, with the remainder being made up of non-neuronal cells called glial cells.

Neurons rely on glial cells for protection and sustenance and form a particularly close partnership with a kind of a glial cell called an oligodendrocyte. Oligodendrocytes have processes that wrap tightly around neurons, insulating them and allowing signals to speed quickly from neuron to neuron. They produce a white substance called myelin which acts like an electrical insulator and these cells can be thought of as the "little white cells" of the brain, with areas of the brain rich in oligodendrocytes having a characteristic white appearance.

Damage to oligodendrocytes is catastrophic to the brain, producing debilitating diseases such as cerebral palsy and multiple sclerosis.

We have been working to identify potential causes of this injury and have found that glutamate release acting upon glutamate receptors is causing damage to the oligodendrocyte cell processes. As a result of this damage the oligodendrocytes are not able to insulate the neurons and this manifests itself in sufferers as an inability to control basic functions such as speech and movement. The work we have completed shows that glutamate receptors are located on oligodendrocyte processes and that over activation of the receptor leads to injury. It is ironic that the receptor that is responsible for transmitting signals between neurons in healthy brain is also the cause of suffering in many cases of neurological disease. The identification of a specific receptor as being responsible is particularly important as it raises the possibility of drugs being developed in the future which may help to reduce injury and the disease states that follow.

http://www.eurekalert.org/pub_releases/ ... 012406.php

Yep, we here have had many discussions regarding the role of glutamate in MS. The most recent one (which you might find interesting to review) was just a little while ago under the thread called "Apoptosis".

They have found that excess glutamate and its receptors plays a large role in Huntington's Disease (HD). I pasted the abstract with regard to that in that thread, also.

Sharon, Robin and I have speculated quite a few times about the role of glutamate, and yes............there are several drugs (oral, too) on the market now that will drastically help to reduce glutamate. They just aren't used (yet) in MS.

Once again, the "patients" are ahead of the "researchers"!

It's nice to see, though, that maybe some of them are catching up to us.

Best!

Deb

EDIT: Oh............and what plays a LARGE part in regulating the glutamate, among other things? My, my.............it's the HPA axis. They just keep going round and round, but they never stop for a second to take stock of where they have arrived at!

Oh, and for those who WOULD like to read up a little more on the connections with regard to glutamate and how glutamate works, etc., I did find something that is written in much better "layman's" terms that I think is interesting for all to take a look at. It is a little easier reading than some of the more technical stuff some of us get into.

It's at: http://www.cnsspectrums.com/article.php3?id=25

Although not a popular notion, I have said to my "friends" at Vandy more than once, that if you look at MS VERY closely and do some physiological comparisons, you could say (and not really be incorrect) that MS can be classified as an "affective disorder".

As you will read quite often, it is stated that it is "puzzling" that MS sufferers often also suffer from clinical depression and the two are tightly interwoven. Uh.........I say........no, it is not all that puzzling!

So, then, let's turn it around. Can or should clinical depression or any of the other affective disorders also be labeled as an autoimmune disease, too? Or should researchers begin to think a little more "out of the box" with regard to MS? Especially given the more recent research that we see, as posted recently here, that is so duplicative of the same research findings that is coming out with regard to the pathophysiology of affective disorders?

And most of the pharmacological agents that work well with regard to regulation of all of this dysfunction being discussed herein, and is highly probable (and proven) to be at the very least neuroprotective, is ............ TCA anti-depressants.

hmmmmmmmmmmm...................


Deb

What is the HPA Axis, what is the connection to glutamate in laymans terms.


I can understand the principal that they make findings and never put the connections together, this is very typical...

For me, the unique discovery from this research is that there are glutamate receptors located on oligodendrocyte processes that are injured through over activation. The researchers sound like they will now focus on finding drugs/substances that act on these receptors, not necessarily on glutamate itself. Any novel avenue of research like this is most welcome in my eyes.

Deb,

You are right that glutamate keeps cropping up.

The article also refers to glutamate being involved in cerebral palsy. Coincidently, there was a research paper a few weeks ago that linked cerebral palsy with viruses (mothers who were infected with a virus during pregnancy were much more likely to have child with cerebral palsy).

The so called 'outbreaks' of MS suggest that MS might be triggered by an infectious agent, perhaps EBV. But how might these lead to too much Glutamate? Any views?

And how does excess glutamate lead to the immune system involvement? Does the glutamate start doing damage and then the immune system gets involved to mop up the mess? And is it the glutatmate that is responsible for the damage to myelin and nerve fibres? I assume that if the glutamate kills off the myelin producing cells then the nerve fibres begin to degenerate because they are not getting the required support.

But why would improvements in EDSS be seen in drugs such as Campath, Rituximab and Daclizumab?

Sorry for all the questions Deb. I just can't get my head round the sequence of all these events.

In layman's terms something happens which creates excess glutamate, this kills of myelin making cells, nerve fibres which are wrapped in myelin start to lose their protective coating, the immune system gets involved and.... This is a very complex story and I now have some sympathy with the researchers. I suppose the test is whether, if you reduce the glutamate level, then myelin making cells can do their job, nerve fibres get the support they need, the immune system doesn't get involved so no more attacks.

The death of myelin making cells before the immune attack was indentified by Prineas and Barnett so would fit with the glutamate theory. Of course the researchers have primarily focused on the immune system attack as the initiator of the problem. The failure of the immune system drugs to stop the underlying progression of the disease would also support the glutamate theory.


I hope, somewhere, that someone is modelling all the possible options for how this disease kicks off, progresses etc. I also hope that there are some small trials of the drugs that you say can reduce excessive glutamate (perhaps you could send me some in the post).

But this research paper looks like a step in the right direction (and is written in a way I actually understand).

Ian

I love the irony of this disease in relation to depression. It sounds as if a vulnerability to depression kicks off the disease, which in turn can make you depressed (because you have a horrible disease), but the solution is to take anti-depressants. It come rounds full circle. I hope this all pans out. A couple of anti-depressants tablets each day would certainly be better than the injectibles or a dose of chemo.

The thing is, Ian, that it is believed that several of these "dysfunctions" (for lack of a better term) are all going on simultaneously, or in such rapid chain reactions that it is almost impossible to isolate any "one" process that can be identified as the "beginning" of MS.

Hence why I also try to stay away from causal relationships. I'm still not certain that will really get anyone anywhere. It's like epilepsy.........what's the "cause" of that? Who cares now? You know why? Because we have effective treatments for it. That's the only reason (in my humble opinion). Do you see a huge push or drives to find the cause of epilepsy? Nope.

So, as I think Robin has mentioned himself a few times, if one or more of these chain reactions can be stopped or reversed or prevented, then we're all the more ahead of the game that way. You can't pin this down to any ONE sequence of events. It won't work.

What I would say is that as many areas as possible should be treated at the same time........something for prevention, something for neuroprotection, AND something for regeneration.

Confusing? Yep! I'm just not certain that an easy way to unravel it even exists.



Deb

Bromley, your question about glutamate and drug trials was intriguing, so I couldn't resist doing a quick check. I came up with 2 possibilities...



Glutamate inhibition in MS: the neuroprotective properties of riluzole.

J Neurol Sci. 2005 Jun 15;233(1-2):113-5. Epub 2005 Apr 20.
Killestein J, Kalkers NF, Polman CH.
Department of Neurology, VU Medical Centre, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. J.Killestein@vumc.nl

In addition to demyelination and damage to oligodendrocytes, axonal injury and neuronal cell death are dominating histopathological characteristics of multiple sclerosis (MS). Still little is known about the cause of the damage. Extracellular accumulation of glutamate contributes to excitotoxic injury of neurons and glial cells, suggesting that the maintenance of subtoxic extracellular glutamate levels may be crucial. Riluzole is a neuroprotective agent that inhibits the release of glutamate from nerve terminals and modulates glutamate, i.e., kainate and NMDA receptors. It inhibits excitotoxic injury in several experimental models of neurodegenerative disease. We performed a small run-in versus treatment MR-monitored pilot study in 16 primary progressive MS patients. The results suggest that riluzole reduces the rate of cervical cord atrophy and the development of T1 hypointense lesions on magnetic resonance imaging in primary progressive MS. The rate of brain atrophy was only slightly decreased. The results indicate an effect on mechanisms involving lesion evolution and axonal loss, but no clear effect on new lesion formation. However, the data suffer from several limitations and must be confirmed in future trials.

<shortened url>



Low dose naltrexone therapy in multiple sclerosis.

Med Hypotheses. 2005;64(4):721-4.
Agrawal YP.
Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Room 153 B MRC, 200 Hawkins Drive, Iowa City, IA 52242-1182, USA. yashpal-agrawal@uiowa.edu

The use of low doses of naltrexone for the treatment of multiple sclerosis (MS) enjoys a worldwide following amongst MS patients. There is overwhelming anecdotal evidence, that in low doses naltrexone not only prevents relapses in MS but also reduces the progression of the disease. It is proposed that naltrexone acts by reducing apoptosis of oligodendrocytes. It does this by reducing inducible nitric oxide synthase activity. This results in a decrease in the formation of peroxynitrites, which in turn prevent the inhibition of the glutamate transporters. Thus, the excitatory neurotoxicity of glutamate on neuronal cells and oligodendrocytes via activation of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid class of glutamate receptor is prevented. It is crucial that the medical community respond to patient needs and investigate this drug in a clinical trial.

<shortened url>

Just an idea from the CpN website but I'll let somebody else (more knowledgeable) explain it.

CpN uses up melatonin and melatonin seems to be important in controlling glutamate ...

Earlier (above), Viper asked what the HPA axis was. That has been asked before, and I believe a good outline in layman's terms was presented in our previous thread: http://www.thisisms.com/modules.php?nam ... hlight=hpa

Go take a look there. I think folks will find it interesting. (I apologize that these threads I am directing you to are mainly the ones where I have posted the explanations, etc. I guess I am just a tenacious researcher! )

How the HPA relates to glutamate (and glucocorticoids) is nicely explained in the article I pasted a link to above (in this thread), i.e. http://www.cnsspectrums.com/article.php3?id=25

Some of this stuff just isn't easy to explain! That's probably why neuros have trouble answering these kinds of questions from patients, now that I think of it! One answer only connects to another, and so on.........

Deb

Ok...........melatonin........another interesting avenue (which all still connects with everything else).

I found a fairly good description of melatonin from http://www.aphroditewomenshealth.com/ne ... news.shtml:



Here is another one:



There is the connection with the HPA (above).

This is where our hormone guru, Sharon, comes in with all of her research.

As was found previously, and I find the below very interesting, because it connects ALL of the different phases (RRMS, SPMS, PPMS) of MS together - the one common thread between them all - is the dysfunction/dysregulation of the HPA:



For a more technical slant:







See why I say that MS might also be able to be called an affective disorder? The pathophysiology and dysfunction that happens in affective disorders is so parallel to what happens pathophysiologically in MS, that it's really bizarre!

And all of the discussions recently and findings being posted lately can all eventually be traced back to the HPA.

And as dignan has shown, there ARE drugs (oral) that can affect any or all of these various dysfunctions.

Interesting..........

Deb

And last but not least..........does the HPA affect the immune system and its function? Yep.



I'd like to point out something with regard to most of these abstracts. Has anyone else noticed that the best research findings with regard to MS hasn't been coming from immunology? It's been from the neuropsychiatric field!

What smells fishy here? ARE MS researchers concentrating on the wrong theories?

Deb

I'm trying to follow this. But one question. If depression is common symptom of MS, wouldn't MS'ers have a higher than average chance of being prescribed antidepressants. And wouldn't that have reduced glutamate and reduced progression (and somewhere, anywhere, been noted or correlated).

No, not necessarily. And it's not just any anti-depressant that affects glutamate. Each drug has different mechanisms of action. It is mainly just a couple of the TCAs (as far as anti-depressants go), not the SSRIs (that will produce a strong enough affect on glutamate to be beneficial for MS). It is mainly SSRI anti-depressants that are prescribed to MSers.

Norepinephrine appears to be strongly implicated in the dysfunction of MS, and SSRIs only act on serotonin. TCAs work mainly on norepinephrine and can have strong side-effects.

TCAs are pretty strong and also affect the immune system to a much higher degree than SSRIs, so they are shied away from being prescribed along with any other immunomodulatory drugs.

Plus, the dose of a TCA to affect depression would have to be too high. It is a low dose of a TCA that is effective, which will not really affect depressive states. Catch 22.

Oh...........and since the AEDs also affect mood (they have been found to be mood stabilizers), and the AEDS are commonly prescribed for MSers for the neuro pain, I think fewer MSers are prescribed anti-depressants than you would think.

Deb

EDIT: I made too general of a statement above. SSRIs do act on glutamate receptors, but they are specific receptors. And each SSRI works differently. And I don't believe SSRIs are strong enough to produce any major differences (for MS disease modification). That's why SSRIs are usually prescribed for depression first, i.e. because they are not as strong and are safer to use in combination with other drugs. TCAs also work on glutamate, but also have a much broader spectrum of action. And once again, each TCA works differently than the other.

I have qualified my statement above. I sometimes tend to not explain clearly enough what I am trying to say. Sorry about that.

Plus, as I have speculated before, it would also take more than just affecting glutamate ALONE in order to show benefit for MS.

You have to do several things at once - affect several other pathophysiologies at the same time, not just reduce glutamate alone and then expect to see improvement.

Deb

EDIT: Glutamate (along with GABA) is also strongly implicated in the mental diseases of schizophrenia and bi-polar, so it's a complex menagerie!