Ion channel control of spasticity

Brocard C, Plantier V, Boulenguez P, Liabeuf S, Bouhadfane M, Viallat-Lieutaud A, Vinay L, Brocard F.Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury. Nat Med. 2016. doi: 10.1038/nm.4061. [Epub ahead of print]

Upregulation of the persistent sodium current in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate INaP and observed elevated expression of voltage-gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with Spinal cord injury.  Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels was associated with an upregulation of INaP in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of INaP. The pharmacological inhibition of calpain activity by MDL28170 (Calpain inhibitor) reduced the cleavage of Nav channels, INaP in motoneurons and spasticity in rats with SCI. Similarly, the blockade of INaP by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI, and it shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of INaP and spasticity.

What has this got to do with multiple sclerosis you say?

I say this is about spasticity in the spinal cord injury and therefore it is relevent to spasticity in MS.
So understand how to control spasticity in spinal cord injury and you may know how to control spasticity in MS.
So in this study they find that in the motor nerves, which are the nerves between the spinal cord and the muscle, that you get alterations in sodium channel activity.

There are nine voltage dependent sodium channels (Nav) and Nav 1.6 is one of the important ones.

They are upregulated in demyelinated nerves and so is one of the targets for sodium channel blockers, which can be neuroprotective because they stop nerve energy depletion caused by the energy required to get rid of sodium from inside the cell.

In this study they find Sodium channels are increased in motor nerves, which may be part of the pathology or as a consequence of firing more often a occurs in spasticity. The sodium channels can be cleaved and deformation of the channel can lead to elevated calcium current and persistent sodium currents leading to spasticity. In this study they find that calpain activation causes the cleavage of the sodium channel leading to spasticity. So this can be inhibited by calpain inhibitors and riluzole can block this sodium curent too…So this is the Nature Medicine….However some medicine I wonder. 

This paper sort of makes my p**s boil……..not because of the paper but it shows the luck of the draw when it comes to referees.

In this study the authors record spasms off a flexor muscle. What’s the surprise in this? 

Nothing as far as I’m concerned but when not a few months ago we where battling with editors from Nature Medicine and referees who say that spasticity is not a problem of flexor (bending muscles) and is just a problem of extensor muscles!
    I say which bit of an extensor is causing these types of problem
                       Yep the frustration of publication.
Next up if riluzole is the exciting solution. What is the question?
In this study they use riluzole to inhibit spasms. This is a sodium channel blocker and glutamate receptor blocker.

Glutamate receptor stimulation increases calcium activation and so together they block influx of sodium and calcium which is going to stop depolarisation (loss of nerve membrane charge which occurs when a nerve fires. Sodium channels open allowing sodium to enter the cells causing the inside of the nerve to become more positively charged compared to the outside = depolarisation. 

So what about spasticity and riluzole. In the rat spasticity can be affected at the dose used…(Click) but “a significant percentage of the animals displayed motor impairments”. This is the problem with sodium channel blockers and glutamate receptor blockers in humans in that they can cause unwanted side effects, AMPA glutamate receptor  were drop and rightly so as they are toxic and NMDA antagonists have not lived up to a useful promise, in terms of spasticity. Glutamate receptor blockers cause desensitization in the system, which limit their use.

So this study indicates that blockers of depolarization can inhibit spasticity….however maybe we can work off the other side and promote repolarisation or hyperpolarisation, which is going to make it difficult for the nerve signal to start. Stop too much nerve signalling and you stop spasticity. 

Indeed this is the basis of other drugs affecting spasticity. GABA A receptor agonists such as benzodiazepines stimulate the GABA A receptor which is a chloride channel and this causes chlorine to enter the cell and this tend to make the outside of the cell more positive than in the inside of the cell. GABA B receptor works via affecting calcium and potassium channels and can result in hyperpolarisation of the nerve limiting nerve signalling. So do this by other means and you may have a winner.

CoI; We are developing alternatives to riluzole to conrol spasticity  

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  • A cynic in me suspects that some of the authors of this published paper may have been among your reviewers…

    • I doubt it because the referees were I will say such idiots, they did not know what spasticity was. Howver one did say H reflexes are not associated with spasticity, and you will note here that the H reflexes were not affected and they dont like our way of quantitatlively measureing spasticity as opposed to some electrophysiological read out guess, but that was off a flexor muscle too. The relationship to H reflex and spasticity can be countered with references starting in the 1950s onwards and we know it does not always respond to drug, but as the H reflexes we were detected were only present in spastic animals the referee (different one) was again an frankly an idiot.

      Such dogmatic narrow minded….don't get me started. Hey Ho onwards and upwards, however this current paper tells me about some biology that I didn't know and can be built into mechanisms which is all the science journals care about. 🙁

  • I suspect like a lot of the publications in nature this will have very little carry over into actual translational research. Wasn't the prediction that the future of science publications is open access journals? What happened to that prediction?

    • So why do you think it was in Nature Medicine…if there is no medical application?

      Riluzole is never going to be used a standard anti-spastic agent or is it?

    • Don't get me started, however I guess mechanism is probably the important factor it suggests how the sodium channel is degradaded isn't this hot stuff?

      However, I agree with you, I don't think there is a future for riluzole as an anti-spastic agent….so not much of a medicine there. It is an out of patent drug.

      We have not looked at sodium channel blockade, but as we know you need them for nerve function and they are poorly tolerated in the population of people who would need them for spasticity.

      We have looked at glutamate receptor antagonists and they can work, but they induce desensitization in the system which stops them working, They can induce marked side-effects at the doses often used and can even kill animals because they can be very toxic (e.g. AMPA antagonists). As for NMDA antagonists the results of memantine (weak NMDA antagonist) haven't been good enough in Ms whn looked at so if we apply the ARRIVE 19 guideline…not much translatability I suspect.

      CoI. I'm biased


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