Inflammation vs. neurodegeneration

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

Postby bromley » Sun Mar 18, 2007 2:27 pm

Finn,

The only drug I'd be willing to try is minocycline, but it is not available here at all.


Surely teenagers in Finland get acne?

I saw a posting from someone with MS who had met with Dr Calabresi (a top doc in MS research). Dr C thought that minocycline had neuro-protective effects. I'm sure you can get some off the internet.

My intention was not too attack the decisions of others. My view on life / risks is perhaps different to others. Someone has to be a guinea-pig on trials to show that drugs are safe / effective. I'm happy to do this if there is a chance of some benefit. PML doesn't concern me one bit. Lady Luck dished out MS to me. so if I got PML or another bad side effect, then someone really didn't like me.

At the end of the day you have decided to take none of the available therapies. And at the end of the day you might be able to turn to me and say "I told you so" if my efforts do not pan out well. There are no winners with MS. You just have to do what your heart / head says.

All the best

Ian
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Cortisol, Inflammation and Neurodegeneration

Postby Shayk » Sun Mar 18, 2007 8:30 pm

Hi everyone

I quite agree that this thread has generated thoughtful discussion with a variety of viewpoints and we’re all still struggling, as are the researchers, with understanding the phenomenon that is “MS”. Thanks for starting it Finn.

In light of the discussion about inflammation and neurodegneration and possible theories, I can’t help but bring up again the theory about HPA hyperactivity and MS. My non-scientific, non-medical background leads me to believe, rightly or wrongly, that this theory could explain some of the inflammation and neurodegeneration that’s evident in MS.

First, the theory,
The Role of the Stress Response Systems for the Pathogenesis and Progression of MS
Insensitivity to glucocorticoid and beta-adrenergic modulation might be involved in overshooting inflammation in MS, whereas hyperactivity of the HPA axis has been linked to neurodegeneration and increased disability.

HPA hyperactivity is roughly the equivalent of high levels of the stress hormone cortisol (as nearly as I can tell) and as the abstract indicates, high and increasing levels of cortisol have been linked to cognitive and physical disease progression in people with MS.

Now, that theory postulates insensitivity to “glucocorticoids”, as an explanation for overshooting inflammation in MS. But recent information suggests that the high cortisol levels in people with MS (aka HPA hyperactivity) might itself invite inflammation. The title of the following abstract is a good one, and the message is basically we all thought steroids were “anti-inflammatory” and it turns out that may not always be the case.

An Inflammatory Review of Glucocorticoid Actions in the CNS
In recent years, the classic view that glucocorticoids, the adrenal steroids secreted during stress, are universally anti-inflammatory has been challenged at a variety of levels….

More recently, chronic exposure to GCs has been found to have pro-inflammatory effects on the specialized immune response to injury in the central nervous system. Here we review the evidence that in some cases, glucocorticoids can increase pro-inflammatory cell migration, cytokine production, and even transcription factor activity in the brain.

So, it seems high cortisol levels could theoretically account for the inflammation in people with MS, in addition to the “glucocorticoid insensitivity” mentioned in the abstract.

Now, on to the HPA hyperactivity (aka high cortisol levels) and neurodegeneration. It’s thought that in about about 50% of the individuals who experience depression (not MS research), it is the high levels of cortisol that precede and contribute to the depression, cognitive impairment and hippocampal atrophy (death of neurons). That idea is best illustrated on page 4 of this article:

Depression, Antidepressants and the Shrinking Hippocampus

The following abstract presents some of the same info about cortisol.

Association of Depression with Medical Illness: Does Cortisol Play A Role?
Data are strongest for a relationship between elevated cortisol and depression, hippocampal atrophy, cognitive impairment, abdominal obesity, and loss of bone density.

And, here’s another.
Hippocampal Volume, Spectroscopy, Cognition, and Mood in Patients Receiving Corticosteroid Therapy
CONCLUSIONS: Patients receiving chronic corticosteroid therapy have smaller hippocampal volumes, lower N-acetyl aspartate ratios, and declarative memory deficits compared with controls. These findings support the idea that corticosteroid exposure appears to be associated with changes in hippocampal volume and functioning in humans.


Anyway, I find the whole “HPA hyperactivity” theory intriguing and thought it belonged in this “thread” since it appears that high levels of the stress hormone cortisol might be a factor in both the inflammation and neurodegeneration in MS.

Enough of that.

Raven and Bromley—I’m thrilled to learn of your tremendous improvements with Campath. That’s wonderful news, I hope it continues well into the future and I wish you both the best.

Finn—I was delighted to learn you’d have your hormone levels tested. You know I think everyone should consider physiologically balanced levels of all hormones. Here I highlighted some potential pitfalls of high cortisol levels, but there’s plenty of pre-clinical evidence suggesting several hormones (DHEA, estrogen, progesterone and testosterone) have significant neuroprotective properties that might be relevant to better managing the MS disease process.

Minocycline appears to offer great neuroprotection as well. I’m sorry and surprised it’s not readily available in Finland.

Take care all. I’ve enjoyed the perspectives and ensuing discussion. "De-stress" :wink:

Sharon
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Re: Cortisol, Inflammation and Neurodegeneration

Postby TonyJegs » Sun Mar 18, 2007 10:37 pm

I am a newbie to this forum.

Frankly speaking I didn't expect to find anything exiting there, partly because I was less active player in MS field for a while. For your information I was (and probably will be) firmly 'attached' to MS from early 80-ties, as professional of course. Since than MS is my favorite disease to deal with.

Gosh, you all made such a great progress in understending of MS, I even got a goosebumps :)
Imagine how hard it was to say anything against 'common view' 10-15-20 years ago, don't even ask about action. Times changed, and this is for good.

Wish every success in this crusade,
Kind regards,
Tony
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Postby finn » Mon Mar 19, 2007 12:30 am

Ian,
bromley wrote:Surely teenagers in Finland get acne?

Yes, I guess they still do. There are tetracyclines available here, but unfortunately minocycline is not one of them.
bromley wrote:Dr C thought that minocycline had neuro-protective effects.

I know, that's why I'd like to try it. Actually, the neuroprotective properties of minocycline were originally discovered here in Finland back in the late 90s, at the University of Kuopio. The group didn't study MS, but ALS and stroke. I've been in contact with some of the group members, and they are still excited about the "broad therapeutic window" of minocycline.
bromley wrote:At the end of the day you have decided to take none of the available therapies. And at the end of the day you might be able to turn to me and say "I told you so" if my efforts do not pan out well. There are no winners with MS. You just have to do what your heart / head says.

Couldn't agree with you more. Except for one thing: I wouldn't ever say "I told you so". It's not my style ;-)

Sharon,
Shayk wrote:You know I think everyone should consider physiologically balanced levels of all hormones.

Yes, you have got me convinced about the possible beneficial effect of balancing hormone levels. Thank you for posting all that valuable information on this board.

Tony,
thanks for your feedback. Welcome to the board!

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 finn » Sat Mar 24, 2007 3:49 am

A recent study shed some more light on the cell molecular processes of central nervous system, and gave me an excuse to bump this thread up. Quote from the abstract:
    "It is generally believed that fast transmitter release is restricted to nerve terminals that contact postsynaptic cells in the gray matter. Here we show in the rat brain that the neurotransmitter glutamate is also released at discrete sites along axons in white matter in the absence of neurons and nerve terminals."
I think that the discovery of axons producing glutamate also in white matter could be important because
  • glutamate overdose is found to be able to cause cell death in central nervous system.
  • it could partly explain changes seen in white matter in MS.
  • some drugs with neuroprotective potential - like minocycline - can inhibit the toxicity produced by glutamate.
  • any study that challenges current understanding may create progress in neurosciences in the long run.
And now the fun part, layman's speculation. I'd like to underline that I don't have any scientific background to tell what is possible and what is not, which makes it really easy to think differently. Anyway, if MS was primarily a neurodegerative disease that starts with changes in gray matter, I suppose one could assume that
  • since axons in white matter are extensions of those in gray matter, negative changes in gray matter might make them produce too much glutamate in white matter.
  • central nervous system might even try to compensate weakened connectivity caused by axonal degeneration with producing more neurotransmitter glutamate.
  • too much glutamate might be able to kill oligodendrocytes (myelin making cells), and maybe the cell death could cause inflammation seen in white matter lesions.
  • a relapse in RRMS might be caused by temporary overproduction of glutamate followed by death of oligodendrocytes and/or inflammation in white matter. And maybe a remission occurs only if central nervous system is able to rewire or reorganize itself (in fMRI studies it has been shown that performing even a simple task requires more activity in MS brain than in healthy brain).
In any case, it is an interesting study. Here's another quote from the article:
    "On the other hand, under pathological conditions the widespread release of glutamate along axon tracts might be harmful: axonal transmitter release is likely to contribute to the ability ofNMDA receptors to mediate ischemic damage of mature oligodendrocytes. Therefore, drugs that modulate transmitter release in white matter might be promising therapeutic targets.

    Axonal transmitter release might also challenge the concept of exclusively directed signal spread in neuronal networks of the CNS. As the axons in white matter are simply elongations of axons in gray matter, it seems likely that extrasynaptic transmitter release also occurs along intracortical axons and that this activates neurons that are not synaptically connected. The resulting spread of neuronal signals would strongly increase the apparent connectivity of neural circuits and could have a significant impact on information processing in the brain."
Any comments?

Be well.

-finn
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Postby TwistedHelix » Sat Mar 24, 2007 6:34 am

Hi there Finn,

As one layman to another, your "speculation" makes absolutely perfect sense. I agree with everything you said.
A couple of questions arise, however, in this picture of white and grey matter which is a new way of looking at things for me: if the white matter is only a part of an axon, why is that? Why does an axon need to be myelinated along just a part of its length? Also, couldn't this hint at a different role for myelin -- if axons are releasing neurotransmitters along their length, and stimulating their neighbours without using a synapse, could myelin function as a shield against overstimulation and confusion in certain areas?

Just a thought,

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Postby finn » Sat Mar 24, 2007 12:35 pm

Hi Dom,

and thanks for your post. Let the gathering of laymen continue:

TwistedHelix wrote:if the white matter is only a part of an axon, why is that? Why does an axon need to be myelinated along just a part of its length?

I'm not sure if I have got it right, but I think that myelinated axons go through the white matter, and there is myelin around them also in other parts of central nervous system, even in the gray matter. And in MS researchers have already found demyelination in the gray matter, too.

TwistedHelix wrote:if axons are releasing neurotransmitters along their length, and stimulating their neighbours without using a synapse, could myelin function as a shield against overstimulation and confusion in certain areas?

Good question. I guess it could. On the other hand, maybe sometimes axons release more neurotransmitters than necessary when trying to make sure that the message gets through in an injured nervous system. And maybe that could explain the overactivity of MS brain seen in fMRI scans.

Be well.

-finn
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Postby Lyon » Sat Mar 24, 2007 12:52 pm

finn wrote:I'm not sure if I have got it right, but I think that myelinated axons go through the white matter, and there is myelin around them also in other parts of central nervous system, even in the gray matter.
Hi Finn,
I'm not sure that I'm 100% correct in this but I've read that the myelin is a fatty substance, whitish in color and it's abundance is the source of the name "white matter". Using that little bit of knowledge I'd have to guess that the density of myelin wrapped axons/neurons/nerve fibers is just less in the gray matter.

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Postby finn » Sat Mar 24, 2007 1:30 pm

Lyon,

Lyon wrote: I've read that the myelin is a fatty substance, whitish in color and it's abundance is the source of the name "white matter". Using that little bit of knowledge I'd have to guess that the density of myelin wrapped axons/neurons/nerve fibers is just less in the gray matter.

Yes, I agree with you. As far as I have understood white matter is mostly myelin, but I'd say the amount of myelin is much smaller in the gray matter.

Anyway, it's probably safe to say that white matter transmits information and grey matter processes it.

-finn
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Postby Lyon » Sat Mar 24, 2007 1:38 pm

finn wrote:Anyway, it's probably safe to say that white matter transmits information and grey matter processes it.
Hi finn,
Again, I'm not an expert and my point isn't to nitpick because I understand what you're saying and I think I generally agree but for the sake of accuracy doesn't it all involve tranmission?

Or maybe it's better to say that effective transmission is essential in either regard?
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Postby finn » Sat Mar 24, 2007 1:45 pm

Lyon wrote:my point isn't to nitpick because I understand what you're saying and I think I generally agree but for the sake of accuracy doesn't it all involve tranmission?

Well, maybe it can't be called nitpicking, but definitely thread hijacking ;-)

Or did you have something to comment on the subject?

-finn
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Postby Lyon » Sat Mar 24, 2007 3:07 pm

finn wrote:Or did you have something to comment on the subject?
Man, you Finns really get to the point, don't you?

No, no comment.

Like you, I read it and was left with no idea what it all meant or if it even relates to the MS process ;)

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Postby finn » Sat Mar 24, 2007 11:33 pm

Bob,

Lyon wrote: Man, you Finns really get to the point, don't you?

Well, we tend to be quite straightforward people. To tell you the truth, sometimes it might even cause some problems when communicating with the rest of the world.

Lyon wrote:Like you, I read it and was left with no idea what it all meant or if it even relates to the MS process ;)

Yeah, but it was nice reading, wasn't it?

Seriously, like I wrote earlier, the discovery of glutamate production also in the white matter might be able to explain many things related to the pathology of MS.

-finn
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Postby TwistedHelix » Sun Mar 25, 2007 6:06 am

I must admit to a bit of confusion here: it has always been my understanding that there is no myelin in the grey matter; this from Wikipedia:

"Grey matter is composed of unmyelinated neurons as opposed to white matter (myelinated neurons). It has a grey brown color which comes from the capillary blood vessels and the neuronal cell bodies"

So the item you linked to, Finn, which mentioned demyelination in grey matter, seems to contradict this.

The discovery that neurons release transmitters along their length paints a revolutionary picture of brain activity: previously, they had only been thought to communicate at the synapse but now it appears the brain is flooded with neurotransmitters. That's what I meant by suggesting a new role for myelin -- that it keeps out this deluge to keep the signal carrying pure, and keeps in the transmitters which are released by the neuron in order to boost the signal it is carrying. After all, in the grey matter it would be ideal for the dendrites and cell bodies to be suffused with neurotransmitters because this would be just the right environment for information processing, complex thought, and the vagaries of emotion, whereas in the white matter neurons carrying sensory and motor signals would need to keep their information "clean". 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,

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Postby finn » Sun Mar 25, 2007 11:22 am

Dom,

in situations like this I really wish I had even some solid knowledge on neurobiology (and maybe a microscope, a scalpel, and a brain in a dish...). On the other hand, occasionally it seems like professionals don't know that much for sure about what's really happening in the central nervous system, either. I suppose they found small amounts of myelin in the gray matter for the first time only a couple of years ago, and the study of demyelination in the gray matter in MS brain was dated january this year. "The times they are a-changin'", hopefully fast.

TwistedHelix wrote:The discovery that neurons release transmitters along their length paints a revolutionary picture of brain activity: previously, they had only been thought to communicate at the synapse but now it appears the brain is flooded with neurotransmitters. That's what I meant by suggesting a new role for myelin -- that it keeps out this deluge to keep the signal carrying pure, and keeps in the transmitters which are released by the neuron in order to boost the signal it is carrying.

Good thinking. Myelin is supposed to be there to protect axons, but maybe it also protects, boosts, and supports neurotransmitters in order to keep the signal pure. I like the idea.

But what if more than being a linear process, signalling would be based on a matrix like structure (broken English, sorry. I hope you'll get what I mean)? Then, if there was something wrong with the primary route for the signal, the axon might try to find alternative routes by spreading more neurotransmitter around itself in the area where the problem occured. That could explain both lesions with dead oligodendrocytes, and the imaging finding that performing similar tasks occupies MS brain more than healthy brain.

TwistedHelix wrote:After all, in the grey matter it would be ideal for the dendrites and cell bodies to be suffused with neurotransmitters because this would be just the right environment for information processing, complex thought, and the vagaries of emotion, whereas in the white matter neurons carrying sensory and motor signals would need to keep their information "clean".

Couldn't agree more. Processing thoughts, emotions, senses and movement at the same time surely takes all available neurotransmitters.

TwistedHelix 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.

Yes, like a drugdealer said to another in a brilliant TV-series, "true that". I'd say one big problem is that the idea is more or less against the concensus opinion. Instead of demyelination, the first pathological event would be some kind of damage in neurons or axons.

Be well.

-finn
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