Canada & the Netherlands

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

Canada & the Netherlands

Postby OddDuck » Fri Oct 07, 2005 8:24 am

As mentioned to Bromley in another post, here is something I found today that supports the research being done in the Netherlands. The positive spin with this is that finding chemical agents (drugs - yes, desipramine being one of them) that will likely prove efficacious should be fairly easy. IF, as Bromley so rightly noted, we can get the researchers OFF of the immune system for a bit, and onto this area.

Here is a portion of what I wrote in an email to someone this morning:

I know I'm a pest about this (well, I haven't been in quite a while, I guess), but since more and more substantiation is coming out now from others with regard to (early) axonal injury in MS and the need for protection, etc., and HOW it can likely be accomplished, I still have to say that desipramine MUST have some use in progressive MS particularly!

The Netherlands are so close to my theories, it isn't even funny! And now I see Canada has jumped on board recently, also (pasted below). So, I guess I'm not completely crazy.

In addition, and I know you already know this, glutamate has also become a centralized theme in MS, along with the HPA axis in progressive MS, etc. etc. And desipramine reduces (and/or regulates) glutamate - that's a given. (Among many other MOAs that should prove beneficial for progressive types of MS........IF any of the theories about progressive MS are on-target, of course. All of which I have stated many times, so I won't reiterate.)

Anyway..................just keep it in mind.............. (Still, desipramine takes at least one year of application before any real evidence of benefit might be exhibited. AND dose is crucial.....LOW dose....has to be low dose - I'd say no more than 50 mg. a day - 75 mg. MAYBE.)

Plus, I still say if you throw in levetiracetam along with desipramine (since levetiracetam inhibits CA+ influx even better than desipramine does, AND raises BDNF better, too).............you might really have something worth looking into!

Bottom line,..............as per my prior notes, etc. etc............MAIN THEME: desipramine for axonal protection and regeneration! Levetiracetam for additional neuroprotection. (Take anything to do with me out of the picture totally. That's coincidence.) Plus, it has been found lately that desipramine shows benefit for Huntington's chorea (and not for depression, but for actual neurological application.)

Here is another substantiation below (although, I would be EXTREMELY careful about mixing desipramine with the interferons......extremely careful. But the interferons aren't of much use in progressive MS anyway, so that takes care of that. Plus, desipramine itself has immunomodulatory MOAs, and inhibits TNFa and IL1b, and raises IL10 - good for strengthening the BBB without such a high risk of adverse events; so the interferons shouldn't be all that necessary anyway.)

You have to admit, all of this almost makes MS appear to be an affective disorder, doesn't it? Pretty doggoned close!

Desipramine sure appears to be a much lower risk level for clinical trials (or bench studies) than what is being experimented with now, doesn't it? Anyway, just some renewed thoughts. Of course, nobody will get rich off of this, that's for sure.

*************************************

J Neurol Sci. 2005 Jun 15;233(1-2):3-13. Related Articles, Links


General mechanisms of axonal damage and its prevention.

Stys PK.

Division of Neuroscience, Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4K9. pstys@ohri.ca

Axonal degeneration is a prominent pathological feature in multiple sclerosis observed over a century ago. The gradual loss of axons is thought to underlie irreversible clinical deficits in this disease. The precise mechanisms of axonopathy are poorly understood, but likely involve excess accumulation of Ca ions. In healthy fibers, ATP-dependent pumps support homeostasis of ionic gradients. When energy supply is limited, either due to inadequate delivery (e.g., ischemia, mitochondrial dysfunction) and/or excessive utilization (e.g., conduction along demyelinated axons), ion gradients break down, unleashing a variety of aberrant cascades, ultimately leading to Ca overload. During Na pump dysfunction, Na can enter axons through non-inactivating Na channels, promoting axonal Na overload and depolarization by allowing K egress. This will gate voltage-sensitive Ca channels and stimulate reverse Na-Ca exchange, leading to further Ca entry. Energy failure will also promote Ca release from intracellular stores. Neurotransmitters such as glutamate can be released by reverse operation of Na-dependent transporters, in turn activating a variety of ionotropic and metabotropic receptors, further exacerbating overload of cellular Ca. Together, this Ca overload will inappropriately stimulate a variety of Ca-dependent enzyme systems (e.g., calpains, phospholipases), leading to structural and functional axonal injury. Pharmacological interruption at key points in these interrelated injury cascades (e.g., at voltage-gated Na channels or AMPA receptors) may confer significant neuroprotection to compromised central axons and supporting glia. Such agents may represent attractive adjuncts to currently available immunomodulatory therapies.

Publication Types:
Review

PMID: 15899499 [PubMed - indexed for MEDLINE]
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Advertisement

Postby dignan » Fri Oct 07, 2005 9:12 am

Nice detective work as always. I think what you're saying also ties in with this research I posted on a little while ago. This seems to be an important area of research which thankfully is starting to receive plenty of funding.

http://www.thisisms.com/modules.php?nam ... pic&t=1441
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 3:00 pm

Postby bromley » Fri Oct 07, 2005 2:09 pm

OddDuck,

I didn't study chemistry at school so the article could have been written in Greek. But I sort of got a sense of what they were saying.

I have posted the following before but there may be a link to your article and I'd be interested in your view of the drug being trialled.

http://www.mssociety.org.uk/research/ms ... o2005.html

I get confused with the term 'channels'. And, there are various chemicals which are cited as possibly causing the damage to the axons e.g. nitric acid, potassium, glutamate, sodium.

But neuro-protection still looks a better bet than keep fiddling with the immune system. I could cope with temporary (reversible) disability caused by the immune response but it's the permanent stuff caused by axonal degeneration that is difficult to take.

Bromley
User avatar
bromley
Family Elder
 
Posts: 1887
Joined: Fri Sep 10, 2004 3:00 pm

Postby Melody » Fri Oct 07, 2005 2:21 pm

That's what I've been saying get rid of the inflammation and the symptoms go away. Different foods do that it doesn't have to be drugs. We do have control of the inflammation if we want it. As to the sodium angle well that is pretty much eliminated if you don't eat processed food and you don't add salt. Salt water fish might come into play here though. I'm going on holidays but will check on it when I get back.Turmeric,Garlic,Onions,cold water fish as well as many other's reduce inflammation. :wink:
John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
User avatar
Melody
Family Elder
 
Posts: 431
Joined: Sun Apr 03, 2005 3:00 pm
Location: Ontario Canada

Sorry couldn't leave you hanging for a week

Postby Melody » Fri Oct 07, 2005 2:38 pm

Anti-inflammatory Foods

Did you know that certain foods act in the same way as anti-inflammatory drugs? The omega-3 fats in salmon, herring, anchovies, flaxseed, walnuts and omega-3 enriched eggs control hormones called prostaglandins that are responsible for the inflammation process. What you eat and what you don’t eat can help you control inflammation.


Inflammation not only causes stiff, sore joints in arthritis, but it also plays a big role in heart disease. It is scientifically well established that inflammation in the arteries is involved in the growth of plaque which builds up on artery walls causing atherosclerosis (blockage of arteries). Inflammation can be the “final straw” leading to a heart attack. Fatty plaque that is inflamed ruptures and forms blood clots which will block blood flow to the heart.


Scientists are also finding that the growth of certain types of cancers can be inhibited by reducing inflammation. Chronic inflammation is linked to the development of high blood pressure and diabetes. Foods with high glycemic index levels not only increase blood glucose levels, but also increase inflammation. There is also evidence that inflammation in the brain damages nerve cells and may contribute to dementia and Alzheimer’s disease.

Those with painful arthritis know they have inflammation, but is there a way to check for chronic inflammation in your arteries? There is a protein in the blood called C-Reactive Protein (CPR) which is a key marker for inflammatory diseases. High levels of CPR are now considered an indicator of a person’s future risk of heart disease.


The good news is that your diet can go a long way to reduce CRP levels in your blood.



Fish



Cold water fish such as salmon, herring, anchovies, mackeral and sardines contain the omega-3 fats DHA and EPA that act much like anti-inflammatory drugs to control the prostaglandin hormones. Studies show that fish and fish oil reduce heart disease by controlling arrythmia, blood clotting and inflammation. A Danish study of people with arthritis revealed that an average of 4 ounces of cold-water fish daily decreased morning stiffness, swollen joints and general pain after 6 months. Other research is showing that omega-3s found in fish may also reduce the inflammation in asthma and psoriasis as well as reducing the growth of some cancers.


Ground flaxseed and walnuts



Plant-based, omega-3 fatty acids reduce inflammation according to a study published in the Journal of Nutrition. Supplementing diets with 2.3 ounces of walnuts and ground flaxseed reduced levels of CPR in the blood.


Omega-3 enriched eggs

Sold under a number of different brand names, omega-3 enriched eggs are on the market in various parts of the country. These eggs are the same as regular eggs except they contain higher levels of omega-3. They can provide approximately 1/4 to 1/3 of the recommended daily intake of omega-3 fatty acids.

Reduce omega-6 oils

It is important to limit the omega-6 fats because they cause the inflammation response. Omega-6 fats are found in corn, cottonseed, safflower and sunflower oils as well as in processed foods (e.g. boxed rice and stuffing mixes, frozen foods and desserts).


Cut back on high fat means and dairy products



Diets that include too much saturated fat such as meats and dairy products increase CRP, the biomarker of inflammation. One American study found that eating too much protein and not enough carbohydrate increased CRP by 61%.


Lose body fat

Achieving and maintaining a healthy body weight is a very effective way to reduce inflammation. Research shows that fat tissue produces compounds that increase inflammation. Obesity is a risk factor for heart disease, hypertension, diabetes, certain types of cancer and arthritis.


Avoid foods with a high glycemic index



Gycemic index (GI) is a measure of how fast a food breaks down into glucose. Foods with a high GI such as potatoes, white rice, sugar and highly processed cereals increase blood glucose and inflammation.


Eat enough fibre



The U.S. National Health and Nutrition Examination Survey involving 3,920 participants showed that dietary fibre was associated with lower levels of CRP, a marker of inflammation.


The bottom line



A healthy diet can reduce inflammation:



Eat plenty of vegetables, fruits and whole grains along with 2-3 portions of cold-water fish every week.
Choose olive and canola oils (monounsaturated fats) instead of corn, sunflower, safflower and soy oils (polyunsaturated fats) more often.
Keep saturated fat and trans fat intake low
Add ground flaxseed and walnuts to your diet
Consider switching to omega-3 enriched eggs
Related Information

<shortened url>


Just do a google search of
reduce inflammation + foods
and you will get all sorts of help if you want the newest out enter
reduce inflammation + foods + 2005
John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
User avatar
Melody
Family Elder
 
Posts: 431
Joined: Sun Apr 03, 2005 3:00 pm
Location: Ontario Canada

Postby OddDuck » Sat Oct 08, 2005 5:40 am

Melody,

That isn't the type of "sodium" they are referring to. This is cell sodium, which has nothing to do with dietary issues. You want to maintain neuronal sodium density within cells, and inhibit calcium influx (among MANY other things) in order to protect axons. This is talking about how ion channels work - cellular level. It all has to do with electrical voltage of cells and neurons and the synapses, etc. You don't want the "pump" to become unregulated or have its timing be off, because then you are allowing calcium (Ca) influx and also allowing sodium (K) egress, which is a problem in MS.

The Na+-K+-ATPase is a highly-conserved integral membrane protein that is expressed in virtually all cells of higher organisms. As one measure of their importance, it has been estimated that roughly 25% of all cytoplasmic ATP is hydrolyzed by sodium pumps in resting humans. In nerve cells, approximately 70% of the ATP is consumed to fuel sodium pumps.

Physiologic and Pathologic Significance

The ionic transport conducted by sodium pumps creates both an electrical and chemical gradient across the plasma membrane. This is critical not only for that cell but, in many cases, for directional fluid and electrolyte movement across epithelial sheets. Some key examples include:

The cell's resting membrane potential is a manifestation of the electrical gradient, and the gradient is the basis for excitability in nerve and muscle cells.

Export of sodium from the cell provides the driving force for several facilitated transporters, which import glucose, amino acids and other nutrients into the cell.

Translocation of sodium from one side of an epithelium to the other side creates an osmostic gradient that drives absorption of water. Important instances of this phenomenon can be found in the absorption of water from the lumen of the small intestine and in the kidney.

Depending on cell type, there are between 800,000 and 30 million pumps on the surface of cells. They may be distributed fairly evenly, or clustered in certain membrane domains, as in the basolateral membranes of polarized epithelial cells in the kidney and intestine. ....

Cation transport occurs in a cycle of conformational changes apparently triggered by phosphorylation of the pump. As currently understood, the sequence of events can be summarized as follows:

The pump, with bound ATP, binds 3 intracellular Na+ ions.
ATP is hydrolyzed, leading to phosphorylation of a cytoplasmic loop of the pump and release of ADP.
A conformational change in the pump exposes the Na+ ions to the outside, where they are released.
The pump binds 2 extracellular K+ ions, leading somehow to dephosphorylation of the alpha subunit.
ATP binds and the pump reorients to release K+ ions inside the cell.
The pump is ready to go again. ....

Regulation of Sodium Pump Expression and Activity
Expression of sodium pump activity is regulated at multiple levels and in both acute and chronic timeframes. A functional pump requires synthesis and assembly of both alpha and beta subunits. In many cells excessive beta subunits are produced, making synthesis of alpha the rate-limiting step in expression. It should come as no surprise that such controls are physiologically complex and involve the action of multiple hormones.

Rapid changes in pump activity appear to reflect modulations in kinetic properties, induced by a variety of intracellular signalling pathways. Phosphorylation of the alpha subunit enhances pump activity, presumably by increasing turnover rate or affinity for substrates. A number of hormones stimulate kinase or phosphatase activities within the cell that affect pump activity. Also, it appears that some cell types contain an intracellular pool of pumps that can be rapidly recruited to a functional state in the plasma membrane.

Chronic or sustained changes in pump activity within cells is usually due to increases in transcription rate or mRNA stability. ....





bromley,

Ok...............lamotrigine is getting very close to what I've been saying all along (I still say desipramine is better along WITH an AED, though, because of desipramine's genetic affects and its affects on norepinephrine, etc. (norepinephrine is the "Na" that is talked about in the article I posted above).

Ok, what lamotrigine basically is is something of a combination drug with both anticonvulsant AND antidepressant actions. It appears to also be good for bi-polar conditions. (See where MS keeps coming back around to actually being almost the same thing as an affective disorder?)

Here are some descriptions of what lamotrigine is and its MOAs. It appears to MAINLY only act on glutamate. So, its MOAs are not broad enough for MS, I'd say. But the "concept" of all of my research is there. See what I mean? I'd say this might help with neuronal protection, but not necessarily axonal protection. You would need to combine this with other agents, which is what I tried to stay away from (i.e. an MSer having to take so MANY pills) with my hypotheses.

I'd say you'd want to watch for depression side-effects with this, too, because of its inhibition of serotonin (if you are not bi-polar). Which WOULD make it good for bi-polar disease, because it is less likely then to cause hypomania.

As I said, its main use would be for some neuronal protection, but not axonal. You've got to also stop calcium influx (see my many other epics regarding this), and this doesn't.; not to mention nor does it do all of the other things my many epics have indicated is needed for MS treatment.

Their theories are getting there, though. So...........how long before they DO actually test desipramine and levetiracetam for MS?

Lamotrigine is thought to act at voltage-sensitive sodium channels to stabilize neuronal membranes and inhibit the release of excitatory amino acid neurotransmitters (e.g. glutamate, aspartate) that are thought to play a role in the generation and spread of epileptic seizures.


Pharmacological Properties: Although the relevance for human use is unknown, the following data characterize the performance of LAMICTAL in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic a1, a2, and b; dopamine D1 and D2; g-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC50>200 µM) when tested in rat synaptosomes and/or human platelets in vitro.
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby Melody » Sat Oct 08, 2005 5:43 am

Thanks oddDuck learned something new :D
John was diagnosed Jan 2005. On lipitor 20mg .On Copaxone since July 4,2005. Vitamin D3 2000iu-4000iu (depending on sunshine months)June 10 2005(RX::Dr. O'Connor) Omega 3 as well Turmeric since April 2005. Q10 60mg. 1500mg liquid Glucosamine Nov 2005.
User avatar
Melody
Family Elder
 
Posts: 431
Joined: Sun Apr 03, 2005 3:00 pm
Location: Ontario Canada

Postby OddDuck » Sat Oct 08, 2005 5:47 am

Sure, no problem, Melody. And you are also correct, though. Dietary issues are VERY important in MS!
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby bromley » Sat Oct 08, 2005 11:36 am

OddDuck,

Thanks for all your help. The researchers being funded by the UK MS Society are pretty focussed on neuro-protection and trials are starting, including cannaboids as a possible therapy for slowing / stopping progression. The big grants that the NMSS awarded in August focus on nerve protection and repair - although one of the grantees is looking at minocycline as a possible neuro-protective agent - wish they could make a decision on this one way or the other, as it's been examined for years.

The company I'm watching at the moment is Neuren - a New Zealand company with a focus on neuro-protection. Some of their drugs are in trial so fingers crossed.

Much money is also being thrown at re-myelination as one theory is that once axons loose myelin they degenerate. Any views on this approach?

Sorry for all the questions but I can't imagine that you watch baseball on TV at the weekends.

Bromley
User avatar
bromley
Family Elder
 
Posts: 1887
Joined: Fri Sep 10, 2004 3:00 pm

Postby OddDuck » Sat Oct 08, 2005 12:11 pm

Yeah, bromley............baseball is NOT my favorite. Actually, I was out and about yesterday and went to see a movie with my son.

Remyelination MAY be helpful in some cases, but frankly, what with the newer discoveries about damage in grey matter (where myelin isn't involved) and with evidence that there is axonal damage where myelin isn't even involved, I'm not certain just to what degree of assistance remyelination will provide in the long run.

Gotta protect the axons, in grey AND white matter, is my opinion!

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee


Return to General Discussion

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: Celeste485, grandsons4


Contact us | Terms of Service