Bromley.........I agree TOTALLY with billf!!! These are all very HOPEFUL findings.
And remember, most of us DO have MS, too!
The majority of theories about MS in the recent past have been basically pure guesswork because of very few ways to measure or actually "see" what is going on inside the body with MS. These findings that we are discussing are arriving now not only from "hypothesis", but also from actual TEST results and more exacting methods of measurements, etc. That's the exciting part! The more detail that is found regarding what is happening in different types or patterns of MS, the faster and more effective treatments and therapies they'll be able to create.
And yes, it never WAS claimed that the current treatments available were all that terrific anyway. (I think just about any neurologist will attest to that; hence, why they are STILL doing clinical trials on the CRABs and mixing them up, etc. etc.) They aren't "bad" at treating MS, of course, but do still leave a lot to be desired, as they say.
Hence, all the passionate people like some of us here, raising our voices to researchers and others to start thinking out of the box. Like billf said, I truly believe what we are seeing now is a true upswing and momentum again in MS research!
Oh.........yes..........I truly believe you should see the positive in all this!!
Why don't you look up 'Chelating Agents' on Google and report to us? I think you might find there are some means of controlling heavy metal ions if there is a need to try adjusting them. That might wind up being a new category of drugs for MS treatment if in fact an accumulation of iron or chromium or whatever is causing a problem.
Definitely things can only start looking better the closer a cause can be determined.
Everybody, have a great evening!
" ....While HO-1 gene transfer confers protection against oxidative stress in a number of systems, clearly not all studies support a beneficial role for HO-1 expression. Cell-culture studies have suggested that the protective effects of HO-1 overexpression fall within a critical range, such that the excess production of HO-1 or HO-2 may be counterprotective due to a transient excess of reactive iron generated during active heme metabolism [35,36]. Thus, an important caveat of comparative studies on the therapeutic effects of CO administration versus HO-1 gene delivery arises from the fact that the latter approach, in addition to producing CO, may have profound effects on intracellular iron metabolism." ....
I am a firm believer that knowledge is better than ignorance.
I have been diagnosed with MS for 6 years but even now there are times when doubt and panic take over, I wonder what will become of me.
The only way I know how to counter that is to learn as much about this condition as I can. I feel that by doing so I can make informed choices as to my treatment options, I can ask relevant questions of my healthcare providers and perhaps in some small way, I can contribute to the 'gene pool' of knowledge.
It gives me the feeling that in some small way I have control over the monster. Without the knowledge I have gained through this board and my own research I would not have been able to make the choices that I have, choices that I believe have helped my condition.
Once you get past the 'horror' factor it really isn't so bad.
Wesley mentioned earlier about "chelation". Without doing in depth research on it myself, can anyone tell me what the effectiveness is with "iron chelation" available to us now? (Wesley......you'd probably know the details of this right off the top of your head, right?)
Could it be a fairly simple procedure, or is iron deposition something that would be difficult in any manner to reverse or treat? You would almost think that dietary considerations would play a big role itself, but I could be way off-base thinking that - again, I have not researched this yet.
(I believe we've all read things about mercury chelation. That appears to be something that is not impossible at all, so I'm suddenly curious regarding iron.)
It may be that HO-1 is over-expressed by the glial cells in MS adding to their apoptopic effect.The products of the heme oxygenase reaction, free ferrous iron, carbon monoxide, and biliverdin/bilirubin, are all biologically active molecules that may profoundly influence tissue redox homeostasis under a wide range of pathophysiological conditions.
<shortened url>The ho-1 gene is also upregulated in glial cells within multiple sclerosis plaques
It kind of brings me full circle and back to activation of the microglia as the primary event in MS.
(And on a personal note for a second, this is TOTALLY interesting to me, as this mirrors so amazingly what MIGHT be the process that is going on with me medically. I won't go into all the details, though. BORING! But it's really starting to get my mind working!)
EDIT: Billf! What a great thread you started here! Kudos!
And I realize not all of you will believe this without my posting how I got there "again", but guys.........I ended up right back at norepinephrine. And I thought I was heading in a totally different direction!
And I swear to you, as far as a treatment that might assist with regulation of glial and microglial activation, glutamate, etc. etc. etc., you name it (i.e. the end part that I referred to previously as the part that I somehow manage to concentrate the most on)..........I ended up back with desipramine again. By accident, again! I wasn't even heading in that direction!
I can't believe it! That does it. I should move to the Netherlands (where their research leads them back to the same place I always end up)!
Ok.........since I AM going around in circles now, I'm going to take a break from this particular exercise, unless I just pose questions or something. I'm certainly not about to bore anyone with more posts that may appear to be trying to "convince" anyone of my particular "theory".
It appears that by different routes we have ended up in the same place. Norepinephrine suppresses microglial activity. (You probably already knew that but it's new to me as I haven't really looked at norepinephrine)
Coincidence? I don't think so...Under pathological conditions, microglia produce proinflammatory mediators which contribute to neurologic damage, and whose levels can be modulated by endogenous factors including neurotransmitters such as norepinephrine
If you ever get time, and/or even care to, you can search and go back through my prior posts (and you'll find the Netherlands abstract that talks about this, too).
Well, anyway........I can totally see where you're at, and it looks like vice-versa, so I need say no more, I'm sure.
Isn't it funny? (And I don't think it's coincidental, either.)
I figured we were on the same page. No matter from which perspective we were coming from. Well, you know what I mean........
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What do we do with this? Is it worth writing up properly and stuffing up the noses of anyone we can find?
I have spent more time trying to disprove what I believe than I have trying to prove it. So far I have been unable to do so. I personally would welcome any input that would cast doubt on these findings.
BTW. One of the things that has always bothered me, that I have been unable to fit into the picture is the age related factor in MS. Why does it mostly appear later in life? Interestingly norepinephrine uptake and clearance changes with age. Another piece in the puzzle perhaps?
I think I agree with Raven that the iron accumulation might be a result but could give a snowball rolling effect to the problems.
But, off the top of my head, heavy metal ions, because of their concentrated charge (+2, +3, or even +4) can act like batteries in the active site of an enzyme, causing electrons to flow towards them through the enzyme. In a typical enzyme reaction this can cause a bond to break in the substrate and another bond to form giving the product. This is why many enzymes use a heavy metal ion as a cofactor, and are typically inactive without the ion. Chelating agents tend to form a cage around the metal ion and mask its strong charge. Heme in hemoglobin is like a chelating agent and is involved in the transport of oxygen in red blood cells. Also porphyrins in tea are like chelating agents because they can mask heavy metal ions and even reduce their absorption from the digestive tract. Outside of a chelating agent cage or an enzyme active site, the metal ions are probably pretty damaging, causing all kinds of undesirable reactions and products (free radicals).
Using chelating agents for therapy goes at least as far back as World War I when mercury poisoning was a side effect of mustard gas poisoning. I can't remember what molecule was used to try to remove the mercury. Also, lead poisoning has been treated with chelating agents but again I don't remember what. One agent we use frequently in research is EDTA to protect DNA and RNA from degradation. It chelates the positively charged metal ions away from the negatively charged DNA or RNA to prevent reactions that would break the DNA or RNA. It also chelates away metal ions from any enzymes that also might produce products that damage the DNA or RNA. Getting the chelating agent into the body and cells is the trick, to get the right solubility.
One problem of multiple transfusions in anemic patients and others is that many of the rbc's given do not survive long and degrade, releasing iron so that there is a build up of iron. This can have numerous side effects in the patient including nausea and CNS problems. There are also a group of diseases (primarily genetic), the thallasemias. These result from improper formation of heme chains so that the hemoglobin formed is inadequate, giving small defective rbc's. As a result, there is an increased number of rbc's made and an increased turnover of rbc's so that there can be a build up of iron again. One chelating agent used is called deferoxamine, but it has to be injected. Apparently it has few serious side effects and these patients can lead fairly normal lives. The thallasemias appear to be found mainly around the Mediterranean and Middle East. I think I even heard that the Middle Ages 'blood letting' treatments originated from trying to treat this disorder (serendipity probably) but then the blood letting got used for just about anything without really understanding the problem it was being used for (sound familiar?). Anyway, the thallasemia patients can also be treated with blood transfusions to give them good rbc's.
You were wondering about the age question, (adult onset). Perhaps it takes time to accumulate DNA damage in microglia that results in their aberrant activation. A bacterial or viral infection may be what it takes to push them over the threshold when they are stimulated into a stress response. Since DNA is repaired on an ongoing basis but in relation to its accessibility, it takes time to accumulate unrepaired sequestered DNA damage that becomes open and active when the cell is finally stimulated or stressed. When cells have been quiescent for quite a while, they get lax in maintaining the integrity of their chromatin.
What I am not seeing in your hypothesis is the female predominance. Throw a few of your thoughts on that question.
Also, why do the microglia of MSers overact? Maybe I missed that point. I'll have to read back over things. Some of the MSers that are posting here could probably come up with a good set of questions your hypothesis or any hypothesis should be able to explain.
I have assumed (dangerous word that, but still.. ) that the female preponderance of MS is due to epigenetic markers on the X chromosome with perhaps X skewing involved as well. It is generally accepted that MS has a genetic component although it hasn't been found yet. A combination of epigenetic markers would be extremely difficult to track down.
Whilst I think of it that's another answer to the age onset question.
As far as why do the migroglia overreact, the answer may lie with the matrix metalloproteinasesThe epigenetic marks a person has could influence disease directly, but they also could affect whether an underlying genetic mutation or genetic variation can actually result in biologic or physiologic changes," says Bjornsson, a physician from Iceland who is pursuing his Ph.D. in human genetics at Hopkins. "We think the latter is going to be very important in explaining the variability of the most common diseases."
For example, if a disease-causing mutation is present in a gene turned "off" by its epigenetic marks, then the mutation can't cause disease. More subtly, alteration of epigenetic marks could "tune" gene expression to cause a full spectrum of effects. Epigenetic variation is also likely to help relate environment and age to disease incidence and risk, the researchers say
Over-expression or under-regulation would result in a cascade reaction amongst the microglia.Matrix metalloproteinases (MMPs) constitute a large family of Zn2+- and Ca2+-dependent endopeptidases, implicated in tissue remodeling and chronic inflammation. They possess broad and overlapping specificities and collectively have the capacity to degrade all the components of the ECM (42, 52). MMPs are produced by many cell types, including lymphocytes and granulocytes, but in particular by activated macrophages (17). MMPs are secreted as proenzymes, which are activated by proteolytic cleavage and regulated by a family of inhibitors called the tissue inhibitors of matrix metalloproteinases (TIMPs), which are constitutively produced by a variety of cells. Changes in actual MMP activity are thus dependent on the balance between production and activation of MMPs and the local levels of TIMPs. In rheumatoid arthritis, pulmonary emphysema, periodontal disease, and inflammatory bowel disease, MMPs are believed to be responsible for much of the associated tissue destruction (4, 35, 43, 50). In addition to their direct effects on ECM proteins, MMPs can exacerbate inflammation by activating the proinflammatory cytokine interleukin-1b (IL-1b) or releasing cytokines such as TNF-a and IL-6 from cell surfaces (1, 21, 23). Their generation of chemotactic fragments from ECM proteins may also contribute to the recruitment of inflammatory cells (22, 40).
Incidentally over-expression of MMP-9 can damage the BBB.
Again it's all theory and conjecture.MMP-9 is suggested to contribute to destruction of the blood-brain barrier and to neuronal injury
BTW. I agree that the presence of iron deposits can lead to further problems through the promotion of free radicals.
EDIT: Having pointed an accusatory finger at MMP-9 I decided to do a little research into it. Firstly it became apparent to me that MMP-9 is identifiable in high quantities in active lesions, there are many references which attest to this. I also came across the following:
<shortened url>Parenteral administration of interferon (IFN)-beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the blood-brain barrier, and of cleaving myelin basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN-beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline minocycline, which has a known blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN-beta by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-beta has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-beta may reduce the side-effects of treatment with IFN-beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.
There are several things of interest in this abstract. Firstly, another thumbs up for the tetracyclines . Secondly it appears that as well as breaking down the BBB, MMP-9 is capable of breaking down the myelin sheath. This raises the possibility that the inflammation seen in RRMS is merely the immune system clearing up the mess and leakage through the BBB.
I really must go and do some work now......
EDIT2: Oh dear, this is turning into an epic now! One last quote...
<shortened url>Specifically, decreased TIMP1 gene expression in the autoimmunity signature suggests increased MMP activity in target tissues as a result of the lack of feedback mechanism.
It appears that the lack of regulation of MMP that I postulated earlier has been identified as a genetic marker in autoimmune diseases.
Wesley: The title of the abstract I took the above quote from is: Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus. I know that you've been looking at Lupus and might find it interesting.
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