Chemical CCSVI…It’s back


So I ask were is VV when you need him. For the new readers, he was the nemesis of this blog, who used to give us a good kicking for not giving the idea about CCSVI=blocked veins that we should have. VV used to put arguments against our arguments and what would he think of this work done in animals. So if we asked “Is this Chemical Angioplasty the next great thing? Would VV give the answer “Next Question”. In this study if follows on from the idea that there is a relative lack of Oxygen in the the CNS tissues (Hypoxia) due to the inflammatory response. And if you put Rats in an Oxygen tank then they accumulate less damage.

Now I suggested the simple experiment is to give people coming into hospital for a relapse an oxygen mask an see if they get out of hospital quicker than if you don’t get oxygen…Too easy.

Nimodipine reduces dysfunction and demyelination in models of multiple sclerosis. Desai RA, Davies AL, Del Rossi N, Tachrount M, Dyson A, Gustavson B, Kaynezhad P, Mackenzie L, van der Putten MA, McElroy D, Schiza D, Linington C, Singer M, Harvey AR, Tachtsidis I, Golay X, Smith KJ. Ann Neurol. 2020 Apr 15. doi: 10.1002/ana.25749. [Epub ahead of print]PMID: 32293054

OBJECTIVE:Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis; EAE) is partly due to CNS hypoxia, and function can promptly improve upon breathing oxygen. Here we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in two MS models.

METHODS:A variety of methods have been employed to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function and tissue perfusion in EAE.

RESULTS:We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE, and a model of the early MS lesion.

INTERPRETATION: Loss of function in EAE, and demyelination in EAE and the model early MS lesion, appear to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function, but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS.

Yep so the idea shown here is that if you dilate the blood vessels with a calcium channel blocker, you get more oxygen to the brain. So that is what is shown. So do people with MS with high blood pressure on medication do better…Come on MSbase do your stuff. Now the implication is this is somehow good for progressive MS, done in experiments that are all about relapse and acute injury. So they use EAE and a form of chemically induced spinal cord injury. So it is funny that nimodipine can limit damage accumulating after spinal cord injury

Early delivery and prolonged treatment with nimodipine prevents the development of spasticity after spinal cord injury in mice. Marcantoni M, Fuchs A, Löw P, Bartsch D, Kiehn O, Bellardita C. Sci Transl Med. 2020 Apr 15;12(539). pii: eaay0167.

Now the dose is 30 times the human dose and one asks why a dose response is not done but there is not much room to get less of an effect

Nimodipine blocks L type calcium channels so is it blocking microglial function or is it working on blood vessels…or a bit of both, So maybe they are on to something.

This image has an empty alt attribute; its file name is ijms-21-01663-g001.jpg

J Neural Transm Suppl. 1990;31:55-71. CNS and PNS effects of nimodipine. Bär PRTraber JSchuurman TGispen WH.

It has been used in EAE already at a lower dose

Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis.

Ingwersen J, De Santi L, Wingerath B, Graf J, Koop B, Schneider R, Hecker C, Schröter F, Bayer M, Engelke AD, Dietrich M, Albrecht P, Hartung HP, Annunziata P, Aktas O, Prozorovski T. J Neurochem. 2018 Feb 23. doi: 10.1111/jnc.14324. [Epub ahead of print]

Then it can also improve remyelination

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis. Schampel A, Volovitch O, Koeniger T, Scholz CJ, Jörg S, Linker RA, Wischmeyer E, Wunsch M, Hell JW, Ergün S, Kuerten S. Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):E3295-E3304..

Now it is said that this is not working by blocking inflammation but would some mild inhibition create some protection of myeining or is it neuroprotection, which is not mentioned here. However it seems there is some anti-inflmmatory effect. In the EAE the inflammation may be gone or it is there pusshing myelin out of the way. But in the LPS animals there looks like some form of anti-inflammatory effect.

If you look on the left the dark blue is the myelin and you can see with the vehicle and nimodipine there are bits of dark blue lost notably the dorsal column. Now in the inflammation induced nerve spinal cord injury they’re looks like a big blob of very dark blue, which looks like inflammation in the grey matter below the dorsal column and this is gone in the nimodipine group.

Anyway what next?

A trial or more animal work?

You could give people nimodipine during relapse and see if there is better recovery. After all there has been nothing except steroids to treat acute injury for the past forty years. Will it work…We did something similar with an N and L calcium channel blocker…This reminds me to publish this.

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  • Hypoxia – is there any possibility that the impact on my MS that I feel (weakening of my impaired leg lasting a week or more) following long-haul flights of 9 hours or more) could be down to this? I put this to my neuro, who poo-pooed the idea but your article makes me wonder…….

    • If it happening something is causing this, but I thougt presurrised oxygen was supposed to be good for MS…(hyperbaric oxygen)

        • My physio had suggested hypoxia but the neuro said it was abnormal strain on the musculo-skeletal system and that if I persisted in wanting to see the other side of the world I’d have to go Business with a flat bed! Which I have done successfully, sadly with a much-reduced number of trips through cost. And now, of course, no trips at all….

      • In my understanding cabin pressure is substantially lower than pressure at sea level, on the order of 2000m above sea, so not hyperbaric at all. Just higher pressure than outside the plane (thankfully😜)

  • Hey! MD, great article and nice to see how seemingly disparate lines of evidence from multiple research investigations are pulled together to make something new. Publish it (but ask someone to check the spelling). It’ll will take me ages to go through the steps and work out how this hangs together. Reading this has been a pleasant distraction from my own research – reformatting a manuscript PNAS bounced at 4:30 on a Friday afternoon by PNAS to ruin my weekend. Probably better than getting it first thin on Monday morning to ruin the entire week. B’stards! No wonder the editors have no friends!

  • Nice post

    Maybe thats the way exercise works in ms ,better oxygen brain flow

    “The researchers gained more insight by analyzing individual cells. They found that restricting exercise lowers the amount of oxygen in the body, which creates an anaerobic environment and alters metabolism”

    These results shed light on several important health issues, ranging from concerns about cardio-vascular impacts as a result of sedentary lifestyles to insight into devastating diseases, such as spinal muscular atrophy (SMA), multiple sclerosis, and motor neuron disease, among others.

    “The question I asked myself was: is the outcome of these diseases due exclusively to the lesions that form on the spinal cord in the case of spinal cord injury and genetic mutation in the case of SMA, or is the lower capacity for movement the critical factor that exacerbates the disease?

    Leg exercise is critical to brain and nervous system health

    Ps: Just finish runnig 1/2hour


  • MD, is there a possibility of having a relationship with vascular diseases in relation to genetic predisposition also for MS? Because I don’t know if this would fit as anecdotal, but I know manu cases of people as the only case of MS in a family, but that the other members of the family have vascular diseases and not autoimmunities. Or would the vascular problem be a consequence of autoimmunity?

  • What a great blog. Lots of scope and energy.
    About CCSVI…
    I’m a bit rusty on the specifics of it but isn’t the idea to prevent MS relapses through the procedure? I didn’t know about oxygen as a treatment *after* coming down with a relapse. As you say, the treatment has always been steroids. I wonder if actually pumping up the O2 to mitigate lesion vulnerability to infarct, necrosis, herniation could indeed become standard of care? Super interesting.

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