Inflammation vs. neurodegeneration

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby Shayk » Sun Mar 25, 2007 3:40 pm

I’ve got a few comments. The first is I totally agree with Dom’s initial comment--
Dom wrote:
As one layman to another, your "speculation" makes absolutely perfect sense. I agree with everything you said.

Finn wrote:
Instead of demyelination, the first pathological event would be some kind of damage in neurons or axons.

I definitely think this is entirely possible (maybe even probable). There’s certainly research indicating damage to both gray matter and axons happens early in the disease course.

I think Bromley originally posted this info about early gray matter involvement.

Gray Matter Damage in MS
a primarily GM-related process may be the earliest manifestation of MS

There’s also info about early axonal damage. Axonal Injury in Early MS
Irreversible brain damage associated with axonal dysfunction occurs at a very early stage in patients with clinically isolated syndromes

So, it seems to me that the first pathological events could indeed be some kind of damage in neurons or axons instead of the myelin. And, this new information you posted about axons producing glutamate is consistent with and seems to complement research Dunmann posted last year.

Unraveling Brain Damage in MS
The researchers showed myelin contains specialized receptors for glutamate
They discovered the surface of myelin has tiny open pores that provide a gateway for calcium to enter. If too much calcium enters, it can injure the myelin and affect our ability to walk, talk or see.

So, I would think these recently discovered pores in myelin present an opportunity for the glutamate produced by axons to exit and damage the myelin just as easily as they provide a gateway for glutamate to enter the myelin and damage axons, i.e., the pores on the surface of myelin provide a portal for the glutamate to go in either direction and cause damage and then the inflammation.

It’s definitely consistent with your speculation Finn where you wrote:
too much glutamate might be able to kill oligodendrocytes (myelin making cells),

and, to take it one step further, Dom wrote:
Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction,

If I understand it correctly this would be something of a neuroprotective response, and when that fails and the myelin is damaged, inflammation follows in an attempt at remyelination(another neuroprotective response). Anyway it's my current understanding inflammation is needed for remyelination.

I think the plausibility of this sequence of events (neuronal and axonal damage initiate the process) is all reinforced by the research that men have thicker myelin and fewer lesions than women but a tendency for more severe disease progression. Could it be that it takes longer for the glutamate from axons to chew threw that thicker myelin men have and finally bring on the inflammation to try and repair it?

There’s also other MRI data that suggests an “inside out” initiation of pathology in MS. On slide 45 of this presentation Advanced Techniques in MRI Daniel Pelletier notes:
MTR changes in normal appearing white matter (NAWM) precede the appearance of new enhancing and T2 lesions—a challenging concept.


Finn—it’s just possible you found and developed an explanation for this challenging concept. Challenging it is, but the times they are a changin’ 8)

Dom wrote:
Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction, though we still don't know how it begins

Did you miss that the stress hormone cortisol causes glutamate toxicity? :wink: Of course I think there are a lot of things that cause glutamate toxicity. Cortisol could be one of them though.

May the gathering of speculators carry on....I don't have a shred of scientific background either.

Take care all

Sharon
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Postby TwistedHelix » Mon Mar 26, 2007 8:22 am

I've been trying to educate myself about glutamate excitotoxicity, and it's very, VERY complicated! First, it came as a bit of a surprise to discover that it may possibly be a normal mechanism used in brain development: I think they're talking about brain plasticity. When we are babies learning to balance building blocks, and maybe even later on in life learning a new sport or skill, certain circuits are reinforced while the ones which are not used die. I'd always assumed they die out through lack of use, but it seems as if those that are over-sensitive are actually killed off through excitotoxicity, (after all, I suppose an overactive circuit is as detrimental as an underactive one). It's always the posts synaptic dendrite which dies .

As far as I can tell, glutamate excitotoxicity is currently regarded as being common to a large number of neurological conditions -- it is seen as the final consequence of a whole host of different circumstances, and it is these circumstances which determine the nature of the illness or condition you have. For instance multiple sclerosis, stroke and ischaemia, Parkinson's, Huntington's, ALS, Alzheimer's and direct physical injury all terminate in this process.
Dietary intake of monosodium glutamate, hydrolysed vegetable protein or aspartame are synergistic, (in other words, sub-toxic intake of more than one can still lead to toxic amounts), and can all raise glutamate. Normally, they will raise serum levels but not brain levels, however, I can't help wondering what would happen if you had a leaky BBB......?

The actual cause of death in glutamate excitotoxicity is calcium overload, but it's not simple: a cascade of events is unleashed which just makes things worse -- a whole host of enzymes is released like phospholipase A, which generates platelet activating factor, which activates the release of more glutamate. Also arachidonic acid, which prevents the reuptake of glutamate, thereby exacerbating the stimulation of glutamate receptors, which then go on to release more arachidonic acid. This acid also forms oxygen free radicals, which activate phospholipase A... round and round...

Conditions like hypoxia and neurodegenerative disorders also reduce levels of ATP, which is used to transport calcium and power the sodium potassium pump and therefore affects the sodium gradient, (the difference between one side of a membrane and the other), this gradient is crucial for the antiporter, which shifts excess calcium out of a neuron.
Did I say complicated? This is just the start!! My head is spinning, so I'm going to go now and watch some children's TV -- I need to learn some SHORT words for a change!

Dom.
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Postby TonyJegs » Mon Mar 26, 2007 9:52 pm

I would like to add some information for this topic.

Myelin was 'invented' not for axonal insulation, axon is not a wire, the main purpose - increase the speed of the impulse. Also it serves for signal speed modification purpose. Thickness and gaps (their number and intervals between them) are not constant, they vary during the lifetime of axon-myelin complex.

Myelin damage is primary for MS, axons survive up to 8-10 years (all terms approximate of course, just watch the scale)
Myelin damage could be reversible if treated in first hours, say like a stroke. If MS patients could get this help when they need it most, the damage will be minimal.
(It was somewhere on the net last year, a letter from the MS patient from New Zealand - he waited for neurologist consultation ONE MONTH since first symptoms of relapse appeared!)

Myelin is present in whole nerve system where is a demand for selective increase of the signal, times really matter, imagine for ex. walking, to keep it functional a lot of different neurons (not from one local point) must fire the set of signals to create an ansemble/array for this particlular movement. Slight delay of one signal may couse the interraption of the moving pattern, etc.

Myelin in gray matter was forever, I think it was seen from the beginning of the 19th century.

There are at least more than 30 neurotransmitters in the brain, all of equal (more or less) importance. That why attempts to modify the quantity (via different mechanisms) of single one will lead to failure to control the whole complex (for ex. depression drugs).
U can think about neurotransmitters as an analogic way of operations, compare the synaptic way as a digital one, of course it is more complex :)

Matrix scheme of operation of the brain was proven many years ago. We memorize this way.

Any medication which interferes the inflammatory cycle will have influence on MS.

Functional (normal) demyelinization/remyelinization is a part of brain development and plastisity, we are who we are as a result of this process. Any drug who alters this process (de-/re-myelinization) will have long -term impact on the brain function.

As an any other living organ contant changes in brain are natural, of course the brain has a bunch of tools for removing old/damaged parts and for reconfiguration of the stucture on demand.

It is pretty difficult to do something with the brain using one single drug because of enormous variety of receptors, complexity of interactions, etc.

More grugs on the market - more tools we have to work with. U can't fix Bentley with bicycle wrench only. Most important thing in using medications - it's PROPER use.

Sorry, the subject is HUGE, can't cover everything.

Kind regards,
Tony
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Postby finn » Mon Mar 26, 2007 11:37 pm

Sharon,
thank you for sharing your thoughts. Very interesting post!

Shayk wrote:I definitely think this is entirely possible (maybe even probable). There’s certainly research indicating damage to both gray matter and axons happens early in the disease course.
---- clip ----
So, it seems to me that the first pathological events could indeed be some kind of damage in neurons or axons instead of the myelin. And, this new information you posted about axons producing glutamate is consistent with and seems to complement research Dunmann posted last year.
---- clip ----
So, I would think these recently discovered pores in myelin present an opportunity for the glutamate produced by axons to exit and damage the myelin just as easily as they provide a gateway for glutamate to enter the myelin and damage axons, i.e., the pores on the surface of myelin provide a portal for the glutamate to go in either direction and cause damage and then the inflammation.
I appreciate you reposting those links. Good stuff. It was you who originally posted the "inside out" vs. "outside in" study here a while ago, wasn't it? It showed that axonal degeneration could cause demyelination in an animal model, and it wouldn't always have to be the other way around. I remember being very impressed by it.

Shayk wrote:when ... the myelin is damaged, inflammation follows in an attempt at remyelination.
Somebody wrote somewhere that "any tissue damage is followed by inflammation". To me it makes much more sense than thinking that the whole destructive process in MS would start with inflammation. As it has already been suggested, inflammation may have many beneficial properties in MS, and demyelination caused by it can only be concidered as "collateral damage".

Shayk wrote:Anyway it's my current understanding inflammation is needed for remyelination.
It might be safer to only state that inflammation creates beneficial circumstances for remyelination ;-)

Shayk wrote:I think the plausibility of this sequence of events (neuronal and axonal damage initiate the process) is all reinforced by the research that men have thicker myelin and fewer lesions than women but a tendency for more severe disease progression. Could it be that it takes longer for the glutamate from axons to chew threw that thicker myelin men have and finally bring on the inflammation to try and repair it?
Yes, I personally think it could. On the other hand, maybe those with more severe disease progression just suffer more neurodegeneration than demyelination? After all, "inflammation defines disease course". Demyelination and remyelination (reverseable disability) have been linked to inflammation, but axonal/neuronal degeneration (permanent disability) hasn't. It looks like the more inflammation, the less permanent disability.

Shayk wrote:Did you miss that the stress hormone cortisol causes glutamate toxicity? Of course I think there are a lot of things that cause glutamate toxicity. Cortisol could be one of them though.
You brought up an interesting issue. I agree with you, "natural elements" such as stress (and hormones, nutrition, etc.) may have a huge effect on the disease onset and proression. As you have stated here several times, somebody ought to study them more.


Dom,
you have really dug deep, haven't you? I'm sure I'm not the only one who appreciates your ability to explain very complicated issues in an understandable manner. Are you sure you don't happen to have a doctoral degree in neurobiology?

Anyway, speculation is much easier when you only have the ability to think and operate on a level of simplified information, like I have :-)


Tony,
thanks for clarifying this stuff for us laymen. A couple of comments, though:

TonyJegs wrote:Myelin damage is primary for MS, axons survive up to 8-10 years (all terms approximate of course, just watch the scale)
I hope you don't mind me asking, but did you mean that the first pathological event in MS would be myelin damage?

TonyJegs wrote:Myelin in gray matter was forever, I think it was seen from the beginning of the 19th century.
Thanks, I needed that ;-)

TonyJegs wrote:Any medication which interferes the inflammatory cycle will have influence on MS.
Did you mean influence on symptoms or long term progression of the disease? If you meant progression, there seems to be also other opinions out there.

TonyJegs wrote:Functional (normal) demyelinization/remyelinization is a part of brain development and plastisity, we are who we are as a result of this process.
Yes, this makes a lot of sense.

Be well.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby TonyJegs » Tue Mar 27, 2007 5:21 am

-finn

1. Yes, myelin damage comes first.
2. Anti-inflammatory drugs reduce symptoms and affect long term changes. They differ.
For ex. steroids is a perfect AID, powerful + reduce the swolleness of the brain. But in a long run steroids BLOCK re-myelination, that's why they must be used for acute situation (onset, relapse) only and shortly.
(I do not understand why people get them on a monthly basis, for what reason?)
Other kinds, as ibuprophen for ex., are safer, but they up to 100 times weaker than steroids.

Kind regards,
Tony
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Postby finn » Tue Mar 27, 2007 8:41 am

Tony,

TonyJegs wrote:1. Yes, myelin damage comes first.
Understandable opinion, especially if one would work for an organisation like Myelin Repair Foundation. Seriously, I don't have any need to argue about it, but by reading the articles and abstracts linked in this thread one can come to a conclusion that there are researchers who have kept their mind open for other possibilities, too.

TonyJegs wrote:2. Anti-inflammatory drugs reduce symptoms and affect long term changes. They differ.
I suppose I'm not the only one who'd like to see at least some long term clinical data to support this claim (study lenght over two years, if possible).

TonyJegs wrote:For ex. steroids is a perfect AID, powerful + reduce the swolleness of the brain. But in a long run steroids BLOCK re-myelination, that's why they must be used for acute situation (onset, relapse) only and shortly.
(I do not understand why people get them on a monthly basis, for what reason?)
One reason for the use of monthly steroids might be a study done few years ago. In it they suggested that steroids used once a month could lessen the amount of relapses as much as interferon beta.

Be well.

-finn
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Postby TonyJegs » Tue Mar 27, 2007 10:45 am

- finn

Thanks for your attention to my post.
Well, I just shared my very independent opinion, that's all.

There is a lot of controversy in medicine (and research), esp. nowadays, when commercialization is on the rise.

Good thing is that truth eventually will work the way out, bad thing is that it will take a lot of time.

Kind regards,
Tony
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Postby Manchester » Tue Mar 27, 2007 11:58 am

TonyJegs wrote:-finn

1. Yes, myelin damage comes first.


Hi Tony,

I am interested in and would like to learn more regarding your reasoning as to why Myelin damage comes first.

I have been following current research that suggests either 1)axonal loss may be separate (at least some of the time) from myelin damage and/or that possibly 2) it could be that axonal injury may trigger myelin degeneration. Simplistically speaking an 'inside to outside' instead of 'outside to inside' mechanism.

Understanding of MS appears to be moving quite quick these days, given that when I was diagnosed over 25 years ago, it was believed then that MS was almost a purely a demyelinating disorder with relative sparing of the axons.

Now, we are seeing more research that implies/states that damage in the grey matter could be caused by a separate process to inflammatory mechanism.

Given that axonal loss can remain clinically silent for so many years after the event, could this not add to the theories that axonal loss may actually come before myelin damage?

Just curious,

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Postby TwistedHelix » Tue Mar 27, 2007 12:17 pm

First, I'd like to try and clear up some of the confusion about white and grey matter, (my confusion, not anybody else's). Grey matter is composed of cell bodies and their dendrites, neither of which have myelin. Communication between structures in the grey matter uses myelinated axons, however, so I suppose there must be some penetration of the grey matter by these axons. This would explain why about five per cent of lesions appear in grey matter.

The description of the myelin sheath as "like the insulation around an electric cable", which we hear ad nauseam, is only shorthand for a much more complicated process -- a bit like when we describe hardened arteries as furred-up water pipes -- it does have an insulating function to reduce charge leakage, but there's much more to it than that:
When you see a depiction of myelin, it resembles a string of sausages, and the tiny gaps between each sausage are called the nodes of Ranvier. When one node depolarises, (shifts its electric charge from the negative towards the positive in response to excitation), it stimulates an "action potential" which can be thought of as a spike or pulse. This spike is enough to trigger depolarisation in the next node, and so on along the entire length of the axon. In this way, signals do not travel in a continuous flow: they leap from node to node in a series of jumps. This is called "saltatory conduction", and is very fast. When a cell membrane has depolarised it needs to get back to its resting potential quickly, and this involves pumping sodium and potassium across the membrane. Because the myelin keeps the nodes of Ranvier so small, it requires much less energy to do this than it would otherwise.

Just a bit more about glutamate excitotoxicity: I find it interesting that damage to JUST ONE neuron is enough to raise the local level of glutamate -- it will begin the cascade of chemical releases and feedback loops that result in neuronal death in the immediate vicinity. This may be why we've heard of so many "causes" of MS over the years: just about anything which can physically damage neurons, from physical injury to viruses to stress, could initiate this process. Because glutamate excitotoxicity is common to so many brain conditions, there has to be something preceding it to distinguish it from other diseases, otherwise they are all the same thing... which wouldn't be bad, because that would mean one treatment would cure all of them!

Riluzole and Lamotrigine are designed to reduce the amount of glutamate, while others have tried to block the glutamate receptors. I'm not sure how far along in development they are yet, so I'm just off to check that out!

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Postby Manchester » Tue Mar 27, 2007 1:40 pm

TwistedHelix wrote:Dietary intake of monosodium glutamate, hydrolysed vegetable protein or aspartame are synergistic, (in other words, sub-toxic intake of more than one can still lead to toxic amounts), and can all raise glutamate. Normally, they will raise serum levels but not brain levels, however, I can't help wondering what would happen if you had a leaky BBB......?

Dom.


I wonder about this too Dom, difficult to find any conclusive proof either way. I stumbled across this article, albeit written in 1999, by Russell L. Blaylock, MD, ( his site, www.russellblaylockmd.com has more information on endotoxins)

It gives some very clear information on the possible role of endotoxins from food in neuro-degenerative conditions.

Food Additive Excitotoxins and Degenerative Brain Disorders

http://aapsonline.org/jpands/hacienda/article27.html

One particular paragraph states...

"But, I have tried to show the reader that there is a strong connection between dietary and endogenous excitotoxin excess and neurological dysfunction and disease. Many of the arguments by the food processing industry have been shown to be false. For example, that dietary glutamate does not enter the brain because of exclusion by the blood-brain barrier, has been shown to be wrong, since glutamate can enter by way of the unprotected areas of the brain such as the circumventricular organs. Also, as we have seen, chronic elevations of blood glutamate can breech the intact blood-brain barrier. In addition, there are numerous conditions under which the barrier is made incompetent."

------------------------------
Find some information on circumventricular organs here http://users.ahsc.arizona.edu/davis/cir ... icular.htm

Interesting reading.

Manchester
Last edited by Manchester on Thu Mar 29, 2007 12:46 pm, edited 1 time in total.
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Postby gwa » Tue Mar 27, 2007 1:59 pm

MSG makes my head feel like it is in a vice.

Aspartame ingestion gives me vertigo.

When people say that these two foods don't affect the brain, I know that they don't know what they are talking about.

If someone that cannot tolerate these toxins were run through an MRI after ingesting them, I am sure their brain cells would be moving around like rap dancers.

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Postby TonyJegs » Wed Mar 28, 2007 12:26 am

Absolutely right Shayk, any tissue damage is followed by inflammation.

Axonal degeneration always cause demyelination in mammals, and there in no other way around. It was known from 19th century. Axon can exist without myelin, myelin can not. Myelin sheaths wrap around the axon on demand only. Myelin per se without axon don’t survive long even in case OL started produce it (in culture), and there is only a bulk of myelin, not sheaths.

Inflammation is not always needed for remyelination. It all size depended (size does matter in this case). When we look at physiological de-/re- myelination it has relatively small volume of “damage”, not so much chemistry involved, signals mostly. Certain cells of the brain clean all ‘mess’ up easily. But if volume of demyelination is bigger than normal, say up to 10 times, than the cascade of events deploying a lot of humoral factors (chemistry) happens. U can compare controlled energy making in a nuclear plant with nuclear explosion or meltdown.
When the volume of damage reach a ‘critical mass point’, the BBB opens up to get access to the site of the damage for other ‘cleaners/helpers’ from the blood stream, trying to control it (therefore preventing axonal destruction/preventing the loss of function). Otherwise the damage area will spread much wider and eventually it could lead to the great lost of the tissue and the following death of the host.
This scenario is uniform for every catastrophic event (stroke, trauma, etc.) in the brain, we can say – build in.

Demyelination causes conductivity block, reversible dysfunction. That’s why the variation of its degree and rapid change of symptoms can fool anyone and makes the diagnosis of MS difficult, esp. at the beginning.
Axonal degeneration creates lasting disability, irreversible dysfunction, and it is very visible clinically. Also I would like to add that axons are much sturdier than thin layers of lipids.

When axonal degeneration happens, the whole length of the axon demyelinates, and it is impossible to create ‘partial limited demyelination’ in certain areas of the axon. At the site of lesion many (hundreds) axons exist, and they run from neurons from different places of gray matter (spatially differ).

Can you imagine the mechanism which can produce a local area of demyelination distantly by some kind of coordinated signals from the axons of different length, different diameter and different origin?
In someone wild dreams only.

Kind regards,
Tony
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Postby TonyJegs » Wed Mar 28, 2007 2:28 am

- finn

TonyJegs wrote:For ex. steroids is a perfect AID, powerful + reduce the swolleness of the brain. But in a long run steroids BLOCK re-myelination, that's why they must be used for acute situation (onset, relapse) only and shortly.
(I do not understand why people get them on a monthly basis, for what reason?)
You wrote: One reason for the use of monthly steroids might be a study done few years ago. In it they suggested that steroids used once a month could lessen the amount of relapses as much as interferon beta.


It is not good enough for me. Please don't get blindfolded with the number of relapses. Score of disability - what is important, which way it goes. It correlates with axonal survival in lesion/scars areas and remyelination.
If the drug (in this case long-term use of steroids) accelerates the disability how it could be good for you? You choose.
When I asked that I do not understand the monthly use of steroids I didn't mean I don't know the subject, I wondered why it's still around.

Kind regards,
Tony
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Postby CureOrBust » Wed Mar 28, 2007 5:36 am

TonyJegs wrote:When I asked that I do not understand the monthly use of steroids I didn't mean I don't know the subject, I wondered why it's still around.
I think you answered your own question, or should be asking more questions. ie "Why are the crabs still around?"
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Postby finn » Thu Mar 29, 2007 2:52 am

Tony,

thanks again for taking the time to share your knowledge and opinions. A couple of comments:

TonyJegs wrote:When axonal degeneration happens, the whole length of the axon demyelinates, and it is impossible to create ‘partial limited demyelination’ in certain areas of the axon. At the site of lesion many (hundreds) axons exist, and they run from neurons from different places of gray matter (spatially differ).
That makes of course sense, but how do you explain this and this finding then? Quotes:
    "Unexpectedly, after adjusting for sex, age and duration of disease, correlations between total plaque load and axonal loss in both the corticospinal tract and sensory tracts were weak or absent at each level investigated. Since there was little correlation between plaque load and axonal loss, the possibility that demyelination is not the primary determinant of spinal cord axonal loss warrants consideration."

    "The degree of atrophy varied in different parts of the cord. Individual lesions played a minor role in local atrophy. Our findings suggest that axonal degeneration, possibly caused by the cumulative number of lesions in the brain and cord, or an alternative atrophic process, is responsible for spinal cord atrophy in multiple sclerosis, rather than tissue loss within individual lesions."
TonyJegs wrote:Can you imagine the mechanism which can produce a local area of demyelination distantly by some kind of coordinated signals from the axons of different length, different diameter and different origin?
In someone wild dreams only.
I bet you couldn't imagine local/minor axonal injury caused by a disease (an infection, maybe), and followed by demyelination seen as lesion. In my wildest dreams, I can.

TonyJegs wrote:It is not good enough for me. Please don't get blindfolded with the number of relapses. Score of disability - what is important, which way it goes. It correlates with axonal survival in lesion/scars areas and remyelination.
If the drug (in this case long-term use of steroids) accelerates the disability how it could be good for you? You choose.
Thanks for your concern, but I personally wouldn't ever use steroids (or interferons, either).

TonyJegs wrote:When I asked that I do not understand the monthly use of steroids I didn't mean I don't know the subject, I wondered why it's still around.
I'm sorry, I didn't understand it was a rhetorical question.


Dom,

TwistedHelix wrote:Just a bit more about glutamate excitotoxicity: I find it interesting that damage to JUST ONE neuron is enough to raise the local level of glutamate -- it will begin the cascade of chemical releases and feedback loops that result in neuronal death in the immediate vicinity. This may be why we've heard of so many "causes" of MS over the years: just about anything which can physically damage neurons, from physical injury to viruses to stress, could initiate this process. Because glutamate excitotoxicity is common to so many brain conditions, there has to be something preceding it to distinguish it from other diseases, otherwise they are all the same thing... which wouldn't be bad, because that would mean one treatment would cure all of them!
Once again, well put!


Manchester,

Manchester wrote:It gives some very clear information on the possible role of endotoxins from food in neuro-degenerative conditions.
That was interesting reading. Thanks for sharing it.

Be well.

-finn
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