Wednesday, 21 November 2012

Research: ion channel as another target for neuroprotection

Epub: Schattling et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis Published online: 18 November 2012 | doi:10.1038/nm.3015

In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the anti-diabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4−/− mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.

The Transient Receptor Potential Melastatin 4 (TRPM4) is an ion channel that controls Calcium signals in excitable and non-excitable cells including nerves. This study indicates that if you block this channel that nerve damage is blocked. This may be achieved with an anti-diabetic drug. We also have data on the value of calcium channel (not TRPM4) blockage as neuroprotectant using differnt drugs, again already used in human conditions other than MS.

The question is how we get existing drugs re-purposed for use as neuroprotectants in MS, if the drug is out of patent. Sure we (academics) have expertise to do the clinical trials, but that is not the problem. It is how we then get them accepted by the regulators and who will pay for this if there is not a drug company behind it. Do academics have to do two phase III trials as appears to be a requirement for pharma. Pharma have teams/companies doing this and they mess up so if academics do this,  some infrastructure is needed. If we cannot get an active drug approved is it worth spending millions doing the studies. 

Is this relevant...yes it is. Phase II simvastatin looked interesting in progressive MS. What about more trials and regulatory submission

17 comments:

  1. Is this relevant to fampradine?

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  2. Profs,

    Does this mean that all the neuro-protective trials usign drugs already approved for other conditions are all doomed to fail i.e. will never be approved for neuro-protections in ms? Sad state of affairs. Surely if one of these drugs proves effective and has a good safety record a doctor (neuro) can precribe it? If not, I can see myself buyingabroad / via the internet.

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    1. No it means there has to be some thought process before you start doing the studies so that they can go through the regulatory process.

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  3. Having taken Simvastatin on the trial I am disappointed that my neuro can't prescribe it (not licensed for MS) and questions the results anyway (don't know how, that was a 'secondhand' remark.

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    1. Just cos you don't know how is not a reason to disbelieve

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  4. Do we really need drugs to protect nerves against inflammatory immune attack? We already have drugs that block inflammatory immune attacks in the brain.

    I would think we need drugs to halt the degenerative process that happens in the absence of inflammation

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    1. You're right. That's what we're working on. It's the next big goal for MS.

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    2. Prof G will be doing a trial of a neuroprotectant in optic neuritis.

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  5. This comment has been removed by a blog administrator.

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    1. I just realized the MS-Stat trial was actually funded by the NIH Research, and charitable money

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    2. May I ask why my comment was removed? Was it by mistake as 2 days ago or this time I wrote something that was not appropriate? Thanks for your clarification

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    3. I did not do it however sometimes this happens by mistake because there is a delete feature under each comment and sometimes this gets touched and it is gone and you cant get it back

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    4. I asked Prof G he did not knowing delete this either. I think the original post was about who funded the trial and you (Ratboy) suggested it was somehting and then changed the details in the second post

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  6. Since simvastatin is so cheap, can't you just get a script for borderline elevated cholesterol? Or just pay cash for the prescription? I'm from US, & I'm not familiar w/ UK healthcare. Do you actually need govt. approval to take a certain medicine? If so, sounds very frustrating & I'd go to the black market. I'm SPMS, & taking 60mg/day of simvastatin. My doctors are open minded and willing to help, but I had to try a few.

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  7. So should I be paying for Simvastatin? Do I need to go back to neuro and ask? SPMSer X

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  8. Is simvastatin going to end up like LDN- where you have to get a sympathetic doctor to give you a private prescription(which you pay for) in order to get it for MS. ( I know LDN hasn't had any trials, unlike simvastatin. I'm just commenting on the mechanics of getting hold of it)

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  9. you would recommend to take the medication even without prescription neuro that there are countries in which you can buy at a low cost, given by any general physician but is taken as reconendable treatment? Thanks for the info on your blog. ....

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