Inflammation vs. neurodegeneration

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

Postby finn » Sun Jul 01, 2007 2:48 am

Sharon,

Shayk wrote:I accidentally happened across an abstract that seems to suggest that autoreactive T or B cells might in fact be protective. It seems to be consistent with the idea that inflammation may be neuroprotective.
Interesting study, thanks for sharing it! I agree with you, there is the possibility that immune system activity in MS is not an "autoimmune reaction" at all.

Shayk wrote:I'm definitely not in the auto-immune camp. ;-) And, if you come across more info from Tsunoda and Fujinami I do hope you'll post it.
Well, this is a consensus autoimmune board now, and I try not to corrupt the spirit by posting more here :-) But if I find something really interesting, I promise I'll make an exception and share it.

Shayk wrote:(btw-- My interest is really in BDNF since some researchers seem to be hard at work trying to figure out how to deliver it to our brains and spinal cords for neuroprotection and to prevent neurodegeneration.)
So far I have come across two things that may be able to increase BDNF: exercise and some antidepressants. Do you happen to have information on other substances that might be able to do it?


Lyndacarol,

Dr Meggs seems to have a strong opinion on the way the immune system communicates with the nervous system. Obviously I'm not able to evaluate the quality of his theories, but I know that there are other ways to interpret the reason for immune system activity, too.

Have you heard about Polly Matzinger and her "danger model"? If she's right, there wouldn't be "autoimmune reactions" at all. Quote:

"In a 1994 article entitled "Tolerance, Danger and the Extended Family", Matzinger went several steps further by laying out the idea that antigen-presenting cells respond to "danger signals" - most notably from cells undergoing injury, or stress or "bad cell death" (as opposed to apoptosis, controlled cell death). The alarm signals released by these cells let the immune system know that there is a problem requiring an immune response. She argued that T-cells and the immune response they orchestrate does not occur because of a neonatal definition of "self", as in the previous model, nor because of ancient definitions of pathogens, as in Janeway's argument, but on a dynamic and constantly-updated response to danger as defined by cellular damage."

So, if Matzinger is right, the immune response would be a reaction to abnormal cell death, not the primary reason for nerve damage.

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 HarryZ » Sun Jul 01, 2007 8:01 am

Finn,

Well, this is a consensus autoimmune board now, and I try not to corrupt the spirit by posting more here :-) But if I find something really interesting, I promise I'll make an exception and share it.


You won't be corrupting my spirit if you post non autoimmune MS theory on this forum :D

Harry
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Postby finn » Sun Jul 01, 2007 8:55 am

Harry, I know you wouldn't ever let me down. Thanks for making my day :D

-finn
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BDNF and Hormones, Sat Fat, Vit E, Curcumin, DHA & "

Postby Shayk » Sun Jul 01, 2007 5:55 pm

Finn

That's more fascinating info:
So, if Matzinger is right, the immune response would be a reaction to abnormal cell death, not the primary reason for nerve damage.

Actually, some of the info on BDNF and MS seems to be consistent with Matzinger’s theory. There’s research indicating relapses elicit a “protective response”, i.e., BDNF levels increase during relapses.

Brain-derived neurotrophic factor in patients with multiple sclerosis
On the basis of recent experimental findings, a neuroprotective effect of BDNF produced by inflammatory cells can be hypothesized during relapses in MS. This can favor remyelination. The reduced production of BDNF by PBMCs of patients with SP MS can contribute to the progression of demyelinating disease and axonal loss in this form.

Regarding the association between low BDNF levels and disability progression the researchers found:
Significantly lower BDNF values were found in unstimulated and stimulated PBMC supernatants of patients with SP MS compared to control subjects. This reduction was greater in patients with a 1-point increase in the EDSS score in the last 6 months compared with that in patients without a progression of the disability score. Reduction in the levels of BDNF was also confirmed in the CSF of SP MS patients compared with R-R MS patients assessed during a stable phase of the disease and control subjects.

Now, to your question:
So far I have come across two things that may be able to increase BDNF: exercise and some antidepressants. Do you happen to have information on other substances that might be able to do it?

Besides exercise and some antidepressants, voila, estrogen and progesterone might also be able to increase BDNF (actually, they may have a role in regulating or modulating BDNF levels).

Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor
The aim of this study is to assess plasma BDNF variations according to hormonal status

BDNF was positively correlated with E(2) and progesterone and negatively correlated with menopausal age. HRT restored BDNF levels to those present in fertile women during the follicular phase. CONCLUSIONS: Plasma BDNF levels are influenced by hormonal status. Modifications in BDNF circulating levels during the menstrual cycle suggest a potential role for gonadal sex hormones (E(2) and progesterone) in regulating neurotrophin expression

And, specific to progesterone, there’s this recent research focused on the brain (mice).
In addition, at a concentration and duration of treatment consistent with our neuroprotection data, progesterone also increased the expression of brain-derived neurotrophic factor (BDNF), at the level of both protein and mRNA.

So, and I think I asked it earlier in this thread, I think it’s very legitimate to once again ask: Is the decline in hormone levels with age a factor that might just contribute to disease progression?

There’s research linking low estrogen and progesterone levels to low levels of BDNF and there’s research linking low BDNF levels to disease progression. Personally, I think it’s becoming harder and harder to totally ignore a possible connection between hormone levels and disease progression. Especially in light of the recent research linking EDSS scores with age. Just my very biased opinion, again. :wink:

And, for people with an interest in diet and supplements, there are some other things associated with BDNF levels. Saturated fat apparently lowers BDNF levels (hello Dr. Swank). Vitamin E can help offset that.
A diet high in saturated fat (HF) decreases levels of brain-derived neurotrophic factor (BDNF),

Supplementation of the HF diet with vitamin E dramatically reduced oxidative damage, normalized levels of BDNF, synapsin I and cyclic AMP-response element-binding protein (CREB), caused by the consumption of the HF diet.

Curcumin might also “normalize” BDNF levels.
Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI.


Omega –3 fatty acids (DHA) may also help “normalize” BDNF levels.
Supplementation of omega-3 fatty acids in the diet counteracted all of the studied effects of FPI, that is, normalized levels of BDNF.

And, Lynda Carol, check this out, low BDNF levels are associated with “insulin resistance”. Per this abstract
It is known that a high sugar, high fat diet leads to reduced brain expression of brain-derived neurotrophic factor (BDNF) which is responsible for maintaining the outgrowth of dendrites. Low brain BDNF levels also lead to insulin resistance.

Finally, Copaxone also appears to impact BDNF levels. And, that’s it for the moment on BDNF.

Finn
Well, this is a consensus autoimmune board now, and I try not to corrupt the spirit by posting more here :-) But if I find something really interesting, I promise I'll make an exception and share it.


I agree with you that it’s a consensus autoiummune board at the moment. However, unlike you I occasionally have to corrupt the spirit, or, so I'm sure it seems to some. But, I continue to think there’s value in different points of view, so I’m glad to know if you find something really interesting that you’ll post it. 8)

There was actually some recent research that doesn't seem to particularly bolster the MS is “auto-immune” perspective. Cerebrospinal fluid oligoclonal bands and progression of disability in multiple sclerosis
Antibody-mediated inflammation is believed to contribute to tissue injury in multiple sclerosis (MS).

There were no differences in presence or number of CSF OCB between patients with significant worsening of disability and stable patients. There were no differences in presence or number of CSF OCB between patients with stable relapsing-remitting MS and patients developing secondary progression during follow-up. The presence or number of CSF OCB does not seem to influence early disease progression in MS.

The beat and the debate will continue I guess--hopefully even occasionally on this board.

Take care all

Sharon
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Postby finn » Mon Jul 02, 2007 3:26 am

Sharon, I found your post extremely interesting and informative. Thanks!

I agree with you, there probably is a connection between age, hormone levels, and the amount of disability.

Let the beat go on :-)

Be well.

-finn
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Postby BioDocFL » Mon Jul 02, 2007 7:56 am

Finn,

You mentioned Polly Matzinger's 'danger signal' hypothesis. I think it's a valid idea and I have been thinking that the Alu sequences serve this purpose as danger signals. There are 500,000 of these short genes scattered throughout the genome and they can be transcribed by RNA polymerase III, which does not require energy (ATP) and does not require a lot of molecular machinery to open up the gene in order to start transcription. Normally 99% of Alu sequences are silent, but with some disruption (perhaps activation of a latent virus that is hidden in the genome), there could be a lot of Alu RNA generated. For some reason there are proteins that anchor these Alu transcripts to the ribosome. Now if the virus has a reverse transcriptase or if an endogenous reverse transcriptase (like some LINE-1 sequences of which there are an estimated 30-60 fully functional LINE-1 reverse transcriptases around the genome) becomes active, as soon as the reverse transcriptase gets translated by the ribosome, it will encounter these anchored Alu transcripts and start reverse transcribing them into Alu DNA. Since Alu sequences are rich in G-C content and the C (cytosines) are usually methylated, the cell will be heavily burdened to methylate them. In fact, I think it would be near impossible to methylate even a small number of them. These Alu sequences, when they escape the cell will appear to the immune system as foreign DNA since they are not properly methylated. They will appear to be bacterial DNA sequences. As I have pointed out before, in lupus there is an enrichment of Alu sequences in the sera of lupus patients and there are auto-antibodies directed specifically against Alu RNA-protein complexes in some patients. I am thinking that some major chromatin disruption, like chromosome fragmentation or loss of some or all of X-inactivation in a cell could open up a lot of Alu sequences to RNA pol III transcription, and even LINE-1 or latent viral reverse transcriptases. The disruption could be due to heavy metal exposure, imbalance in Ca+2 ions, or some cellular stress.

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Postby jackD » Mon Jul 02, 2007 8:26 pm

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Postby HarryZ » Tue Jul 03, 2007 7:54 am



Unfortunately the original cause of the inflammation isn't known and has kept researchers guessing for decades. Also, I wouldn't place too much reliability on results from EAE in that poor MS mouse...we haven't seen any reliable therapies come from that model of the disease, ever!

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Postby viper498 » Tue Jul 03, 2007 10:38 am

Sharon, Finn, and Wesley,

You guys are way too smart. I have no idea what you talking about above!! Way over my head. That is why I don't visit this thread much. It is just way over my head.

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I gave up the quest

Postby jackD » Tue Jul 03, 2007 1:31 pm

I gave up on the quest for the "ultimate cause of MS" and the search for the magic pill.

Especially when so much is known about the mechanisms of destruction of MS and how it progresses.

The two stage theory revals some simple way that these procesess can be blocked or rather slowed.

http://home.ix.netcom.com/~jdalton/ms-two-stages.pdf

For RR MS lowering MMP-9s and a few other things seems a good approach.

1. MMP-9s eat holes in the Blood Brain Barrier(BBB), destroy myelin and cleave/inactivate Interferon drugs.

http://home.ix.netcom.com/~jdalton/Yongrev.pdf

http://www.cnsforum.com/commentedite...9/default.aspx


2. REDUCE MMP-9s ANY way you can - using diet, supplements & secondary effects of other drugs.

Things that reduce MMP-9s (AKA gelatinase B)

VIT D3 .................................REDUCES MMP-9s

RESVERATROL (Grape Skin Extract) ...REDUCES MMP-9s
(NOT Grape SEED Extract)

GREEN TEA EXTRACT(EGCGs)... REDUCES MMP-9s

ALPHA LIPOIC ACID (R-lipoic/ R-Dihdro-LipoicAcid) ... REDUCES MMP-9s

NAC N-Acetyl-L-Cysteine .......REDUCES MMP-9s

STATIN DRUGS (i.e Zocor) .....REDUCES MMP-9s

Omega-3s (ie Fish oil) ...........REDUCES MMP-9s

Minocycline/Doxycycline.........REDUCES MMP-9s

Curcumin.............................REDUCES MMP-9s

Pycnogenol (Pine bark extract)..REDUCES MMP-9s

Chondroitin sulfate (CS) and CS plus glucosamine sulfate (GS) ..REDUCES MMP-9s

Interferon Betas 1a/1b...........REDUCES MMP-9

(of course Steroids ....REDUCES MMP-9s)

***NOTE*** ( gelatinase B = MMP-9) ***NOTE***


3. Cap other inflammatory components like IL-12, Gamma Interferon, TNF-a, IL-1 beta and glutamate excitotoxicity.


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Postby dignan » Wed Jul 04, 2007 8:53 am

I thought the abstract below fit pretty well in this thread...



Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis.

Neurology. 2007 Jul 3;69(1):63-7.
Pascual AM, Martínez-Bisbal MC, Boscá I, Valero C, Coret F, Martínez-Granados B, Marti-Bonmati L, Mir A, Celda B, Casanova B.
Department of Neurology, Hospital Universitario La Fe, Avda. Campanar 21, at Valencia. E. 46009, Valencia, Spain. med004201@saludalia.com

OBJECTIVE: To assess the relationship between the spectroscopically measured axonal damage in the normal-appearing white matter of the brainstem, the total brain T2-hyperintense lesion volume (T2LV), and disability in patients with early relapsing-remitting multiple sclerosis (RRMS).

METHODS: Forty-three RRMS patients and 10 sex- and age-matched healthy controls were prospectively studied for 2 years. T2-weighted magnetic resonance (MR) images and proton MR spectroscopy were acquired at the time of recruitment and at year 2. Brainstem was considered, where large tracts join together, as a suitable region to detect early axonal damage. The T2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) resonances areas were integrated with the jMRUI program, and the ratios were calculated for the sum of the volume elements represented at brainstem.

RESULTS: The basal NAA/Cho ratio was significantly decreased in patients compared with controls. After 2-year follow-up, there was a decrease in the NAA/Cho (-9%; p = 0.002) and NAA/Cr (-13%; p = 0.001) ratios, and an increase in the T2LV (19%; p = 0.043) in multiple sclerosis patients, whereas control subjects had no significant metabolic changes. Significant NAA/Cr ratio decreases were observed in both patients, with and without relapses, whereas T2LV only increased in patients with relapses. The final Expanded Disability Status Scale (EDSS) score correlated with T2LV at baseline, but no significant correlations were found between metabolic values, T2LV change, or EDSS score over the study period.

CONCLUSIONS: Our data reveal an early and progressive axonal damage in relapsing-remitting multiple sclerosis. Axonal loss and T2 lesion volume seem to be at least partly dissociated processes in early stages of the disease.

Pubmed URL
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Testosterone and BDNF, Inflammation and Neurodegeneration

Postby Shayk » Sun Jul 08, 2007 8:11 pm

Finn
I agree with you, there probably is a connection between age, hormone levels, and the amount of disability.

You made my day. :D Now, I’m embarrassed to have to admit that among the hormones, in addition to estrogen and progesterone I totally forgot to mention testosterone as another one that might increase BDNF. Per the testosterone trial results
…..we saw a 'triple whammy' of improved cognition, slowing of brain atrophy, and increases in the production of brain-derived neurotrophic factor (BDNF)," the researcher said.

Specifically, BDNF more than doubled

It seems pretty amazing that going from a “low normal” level of testosterone to a “high normal” level had such a dramatic impact on BDNF levels (and everything else of course) in that trial. And speaking of age, hormone levels, and disability, here’s a link to Wikipedia’s info on “andropause”.

Jack
MS is a two stage disease

The thing that strikes me about the “two phase” idea is that people begin the insidious “neurodegenerative” decline after relapses (inflammation) cease. It seems to be quite evident in the graphs of the progression of MS and it sort of supports the idea that some inflammation may be neuroprotective. Harry, I agree with you that I don’t think the original cause of the inflammation is known yet. Now of course I think they’re finding that the neurodegeneration may be present from the gitgo—maybe even initiate the inflammation. :wink:

Jack
I gave up on the quest for the "ultimate cause of MS" and the search for the magic pill.

Yeah, it’s complicated. I have my doubts about a “magic pill” too. I tend to think there are multiple factors that probably contribute to the “cause” of MS. Thanks for the info on the MMP-9’s.

Brock
Sharon, Finn, and Wesley,

You guys are way too smart. I have no idea what you talking about above!! Way over my head. That is why I don't visit this thread much. It is just way over my head

Well Brock, I must say Wesley is way over my head, and Finn is occasionally over mine, but I have serious doubts that Finn and I are always over your head.

Basically, I think the thread is a discussion about “What kind of disease is MS?” “What is the pathology?" And, how and when do the neurodegeneration, or, as the case may be, inflammation begin? What is the sequence? I think more or less in the “traditional view”, it’s thought that the inflammation destroys myelin, the loss of myelin leads to the loss of axons and the loss of axons results in the loss of neurons, and ultimately there’s disability.

Some of the posts in this thread present research suggesting that may not be the case nor the sequence of events.

Why discuss it? As the title of the thread---thanks first to Finn and then as J. Palace noted: Inflammation versus neurodegeneration: Consequences for treatment
Clearly if inflammation is not the primary event but a secondary phenomenon this has important implications in developing treatment regimes.

And, the info Dignan posted (thanks),
CONCLUSIONS: Our data reveal an early and progressive axonal damage in relapsing-remitting multiple sclerosis. Axonal loss and T2 lesion volume seem to be at least partly dissociated processes in early stages of the disease.

is rather consistent with earlier research Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis
Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis.

This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.


Hope that helps a bit (that is if you read it Brock)

Take care all--I’m still all in favor of early neuroprotection.

Sharon
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Postby viper498 » Mon Jul 09, 2007 5:44 am

Sharon,

Thank you for the executive summary. I appreciate that. I understand the reason for the thread for sure. There are serious implications for all of us if, indeed, axonal degereration is occuring first. How do you get conclusive evidence of this though except for post-mortem analysis?

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11,236 transected axons per cubic millimeter

Postby jackD » Mon Jul 09, 2007 11:53 am

Appears that something besides myelin damage is occurring when you have
"The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions".

jackD

1: N Engl J Med. 1998 Jan 29;338(5):278-85.

N Engl J Med. 1998 Jan 29;338(5):323-5.

Axonal transection in the lesions of multiple sclerosis.

Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.

BACKGROUND: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis.

METHODS: Brain tissue was obtained at from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions.

RESULTS:
Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. 8O The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains.

CONCLUSIONS: Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.

PMID: 9445407 [PubMed - indexed for MEDLINE]
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Re: 11,236 transected axons per cubic millimeter

Postby HarryZ » Mon Jul 09, 2007 1:30 pm

JackD,

Thanks for posting this study,

I guess that despite any kind of steroid or current MS approved medications, it appears that axonal damage continues to march on and cause disability progression. If only someone could figure out what is causing this damage in the first place !!

Harry
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