Although we did not worked on MS but during our hypoxia ischemia studies in GAMT AGAT knockout mouse, we had observed that creatine monohydrate supplementation not only decreases infarct size but also improves the brain function and neuromuscular coordination. Similar response may be expected in MS patients

Your question is very focused and really in the heart of one of the big question about MS and the immune suppressive therapies. I am not a doctor specialized in MS, but I have some experience in animal models and in the recent clinical trials, such as the one conducted here in Cambridge on monoclonal antibody anti-CD52 (namely Alemtuzumab). Probably you have heard about the so called "Protective autoimmunity" (see http://www.nature.com/mp/journal/v15/n4/abs/mp201031a.html): apparently the immune system is not only involved in the immune surveillance of the CNS, but is actually contributing to its dynamics and to its normal function (e.g. influencing the adult neurogenesis in the brain). It is accepted, as you say, that inflammation into the CNS influences the patotrophism of endogenous NSCs towards the site of inflammation/injury. However, could be that a failure in CNS regulated immunosurveillance (because of of failure in controlling their activity, such as in MS) may result in brain malfunction. So, if on one side the autoimmune reaction damages the brain, on the other seems possible that its complete suppression trough therapeutic molecules (in particular monoclonal antibody) should cause a decrease in the ability of the CNS to re-myelinate. On the contrary, I have to say that for example for Alemtuzumab, the first data from the clinical trial, suggest a reverse of the neurodegenerative nature of MS: RR-MS patients seem to improve in their disability status. I know that someone here is investigating how this is possible, if the antibody is increasing for example the endogenous remyelination capacity of the CNS.

Indeed, the debate about the role of inflammation (positive vs negative) is still very active and controversial.

But I am not a big expert and I am not sure that this can answer your question, maybe it is only speculation.

Dear Juliet, I agree with Mateo, that your question is in the center of our concern about the relevence that immunosupressive therapies could have for MS therapeutic intervention.

It is well known that inflammation has also a good side to play. The immunopathology behind demyelination includes T-cell and B-cell driven immune responces. If you suppress these responces then you may loose the generation of nerve growth factors, as BDNF, and the benefits these have on remyelination.

To my opinion the only reason to use immunosupressive drugs is the very aggressive forms of MS and for a short time.

Your question would be true if lesions shrinking are followed by reduction in disability score. As far as I know, it is not the case. MS is a complicated disease and lesions shrinking can not solely solve the problem. Thanks. Simon

My idea is that, as in many other injuries, CNS is able to repair itself. You can increase such intrinsic ability with treatments adressed to increase brain repair without stopping the immune disorder. There are many clear examples about how the CNS is able for itself to repair lesions in MS, at least in the early stages of the disease.

I do agree with you Gareth and in fact is what we do.

Inflammation is an early and key event in regeneration of all tissue damage. However, it is known that intense or chronic inflammation may increase tissue damage, lead to scar formation and cause malfunction of the affected organ. So, Inflammation may have beneficial effect as well as deleterious effect. In the case of MS, treatment with immunosuppressant drugs may be triggering both inflammatory effects. Impairing the progression of symptoms is important for MS patients and, therefore the immune suppression is necessary. But it may also reduce the beneficial effect of the immune system. Our efforts should be focused now in finding therapies that convert deleterious inflammation in to regenerative inflammation.

Dear Juliet, I regret that I didn't read your question carefully before writing an answer. As others said before I think that your question is really interesting and it is difficult to give the right response to it. In my opinion the key points of your question are: what kind of immunosuppressants are you asking about? is it inflammation useful for brain repair? or, it is deleterious?

Classic immunosuppressants, such as corticoids, are usually able for blocking the immune attack to the CNS but they also block reparative neurogenesis. By the way, as Gareth said, adult neurogenesis is restricted to some specific brain areas, but this restriction does not impede that newly formed neurons can migrate towards injured areas or to be integrated in a compensatory plasticity response (we recently published it in Behav Brain Res 2013). Therefore stimulating neurogenesis has to be mandatory. Despite of the negative effect of corticoids on adult neurogenesis, an adequate combination of inhibitors of serotonin uptake and dexamethasone leads to increased expression of EGF and its receptor; and EGF signal induces oligodendrocytes precursors proliferation and differentiation.

Other immunosuppressants, such as azathioprine, have to be inhibitors of neurogenesis, given the putative negative effects that they exert on multiple pathways involved in nucleic acids biosynthesis and the damage that they produce to DNA. But if you are talking about the recently developed monoclonal Abs it is unlikely that they can affect neurogenesis; that is they can block the immune attack without affecting the production of new neurons. In this case, enhancing neurogenesis with hormonal treatments, for instance, may contribute to brain repair. Immune attack blocked and neurogenesis enhanced, this would be the theoretical situation in this case.

With regard to CNS inflammation. Inflammation is a source of a number of cytokines able for stimulating brain repair, but, in my opinion, its negative effects are greater than the positive ones. Inflammation leads to significantly increased production of ROS, and a cascade of cell deaths starts after it. Therefore I think that CNS inflammation has to be avoided in any case (not only in MS, but after any kind of brain injury). Luiz said that our efforts should be focused now in finding therapies that convert deleterious inflammation into regenerative inflammation. This idea is very good, but how to do it? for instance, how to selectively block a number of "bad" cytokines while stimulating the release of those exerting regenerative effects? difficult question. I think that other therapies, such as these I pointed out are more feasible and effective.

Kind regards

Jesús Devesa

I know from personal experience, that even though I have been on beta interferon for years, the lesions come and go, and I still get more and more disabled. Furthermore, the new studies indicate even though fewer lesions occur with people on interferon, copaxone, and the older therapies, that the time of progression for physical disability is the same.

A CURE to repair the myelin damage on the CNS in both the brain and spinal cord and reverse the damage and prevent the CNS attacking itself again would be best.

Lesions in the brain do naturally evolve and regress and at the site of the lesions, scarring from the damaged myelin cause further disability at times e.g. balance

With the progression of MS, I do not trust "modern immunosuppressant therapies".

What are some of the examples of "modern immunosuppressant therapies"?

Enduring the side effects of a "therapy" is the first start but what is it made from, what will it cause the body to do and does it really cease the progression of MS?

For myself, there has only been further scarring and NO regeneration of the brain.

I think there might be signs of hope with the newer therapies. I have heard stories from my neurologist, that some people on Tasabri who were in wheel chairs, are actually walking again. And the newest oral Biogen drug seems also to be helping people. I think time will tell. In my opinion, the newer drugs directly work on stemming inflammation whereas copaxone and beta interferon work through different mechanisms. My feeling about Tsabri, though is that it only prevents the inflammatory cells from entering the CNS, and for his reason I would be afraid of long term usage. For MS, not taking anything for most people, is not an option. The disease is nasty as you know. So I think the benefits outweigh the risks. If you continue to keep having further scarring with no regeneration, if you can afford it, I suggest you take the newest oral drug.

DIMETHYL FUMARATE, capsules, 120 mg and 240 mg, Tecfidera® appears interesting.

Side effects: flushing, skin reactions, nausea, vomiting, diarrhoea and abdominal pain. Less common but more serious side effects of Tecfidera include effects on the kidneys, reduction in lymphocytes (white blood cells) and increased risk of infections.

I think we need more information about this medication and the longer term side effects of this medication e.g. after 5 years and beyond (if it is still effective).

Blood tests, scans etc and gradual physical deterioration definitely confirms clinically proven Multiple Sclerosis on the brain and spinal cord and my ability to function (neuro cognitive tests, EEG, and walking, daily activities e.g. brushing my teeth/shower).

Through all the blood tests and scans, its been 'proven' I do not have a different condition.

Marcia, I'm stimulating the brain by studying so we can still function notwithstanding our physical disability.

I do not know how soon my RRMS will develop to Secondary Progressive MS) - depends on which neurologist I speak to... or as soon as I cannot use my legs or arms.