Blocking Calcium, Should we listen to mouse studies or plough on regardless


Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis.

Witte ME, Schumacher AM, Mahler CF, Bewersdorf JP, Lehmitz J, Scheiter A, Sánchez P, Williams PR, Griesbeck O, Naumann R, Misgeld T, Kerschensteiner M.

Neuron. 2019 Jan 6. pii: S0896-6273(18)31123-1.

Axon loss determines persistent disability in multiple sclerosis patients. Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. We rule out the endoplasmic reticulum (place where proteins are made and formed), glutamate excitotoxicity (a mechanism thought to cause damge in stroke), and the reversal of the sodium-calcium exchanger as sources of intra-axonal (inside the nerve) calcium accumulation and instead identify ruptures of the axonal plasma membrane as the critical path of calcium entry.

Why is this paper relevant?

We have been searching for ways to try and protect nerves from damage.

One way we thing that nerves get damaged is that too much sodium or calcium enteres the cell. If too much calcium gets into a cell it causes the cell to commit suicide. This could happen when too much sodium gets in a cell causing a molecule called the sodium exchanger, which normally kicks out calcium by bringing in sodium, to go in reverse. Alternatively if you get too much of the neurotransmitter called glutamate acting on glutamate receptors causing the increase of calcium entry.

To alter this and save nerves, you can try and block calcium channels, which will stopping calcium entering the nerve cells…which we have done in animals. It didn’t work to our surprise. This study suggests why.

It suggests that the calcium getting into the cell does not get in via calcium channels but leaks in via the cell membrane. So blocking calcium channels may not work to save nerves.

Should we test a calcium channel blocker in MS as it looks good on paper?

Yes and ignore this study?..It is a mouse after all or do alot more work. There are plans for this.

For example

EAE causes less nerves (green) a calcium channel block inhibs EAE, even before it is used in treatment:-(…Look at the graph on the right…the blue line has dropped before drug is given-Who reviews this stuff:-(

However, in animals blocking calcium channels, surpresses the immune system and that is neurorptoective. No immune system in the brain and no damage, However we don’t need to do this as we have agents that do this already.

Indeed we already use a drug that does this on a special type of calcium channel, of which there are lots. This drug is called ocrelizumab, which binds to CD20. But CD20 is a type of calcium channel called ”
 membrane-spanning 4A ” which is essentially only found on B cells. This is why ocrelizumab can cause damage to B cells just be binding to the channel. This is becuase immune cells use calcium for becoming active.

So we have information that says …Schtop! Will and should we listen?

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  • Thanks for the depressing post MD.

    So if I understand this, Ca channel blockers will be useless to stop apoptosis of the axon? Perhaps to stabilize axon earlier, Na channel blockers may help stabilize the axon membrane?

    To stop axon destruction, we will need to somehow stabilize the axon membrane. This sounds like an impossible task. Maybe it would be more worthwhile to replace the failing axon (neuro-restoration) which sounds like an even more impossible task.

    • The question is do we give it a try? That is remembering that mice are not men or women. But this is a very real question?

      However I do not think we have to give up on this approach as I believe we can get at the end result of the cellular equivalent of blocking sodium or calcium channels by other means…we have done it already experimentally.

      • Animal studies in basic cellular physiology don’t necessarily lie. I think this study by Witte et al is important and shows neurodegeneration must be stopped prior to Ca influx as the membrane will already be unstable.

        Focus should be on remyelination which stops addition of additional Na channels and stabilizes the cell membrane or Na channel blockers or axonal regrowth/restoration. Simple task MD?

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