Fampridine and neuroprotection

Boiko N, Kucher V, Eaton BA, Stockand JD Inhibition of Neuronal Degenerin/Epithelial Na+ Channels by the Multiple Sclerosis Drug 4-Aminopyridine.J Biol Chem. 2013 [Epub ahead of print]

The voltage-gated K+ (Kv) channel blocker, 4-aminopyridine (4-AP), is used to target symptoms of the neuroinflammatory disease, multiple sclerosis (MS). By blocking Kv channels, 4-AP facilitates action potential conduction and neurotransmitter release in pre-synaptic neurons lessening the effects of demyelination. Because they conduct inward Na+ and Ca+ currents that contribute to axonal degeneration in response to inflammatory conditions, acid-sensing ion channels (ASICs) contribute to the pathology of MS. Consequently, ASICs are emerging as disease-modifying targets in MS. Surprisingly, as first demonstrated here, 4-AP inhibits neuronal Deg/ENaC channels, including ASIC and BLINaC. This effect is specific for 4-AP as compared to its heterocyclic base, pyridine, and the related derivative, 4-methylpyridine; and akin to the actions of 4-AP on the structurally unrelated Kv channels, dose- and voltage-dependent. 4-AP has differential actions on distinct ASICs, strongly inhibiting ASIC1a channels expressed in central neurons but being without effect on ASIC3, which is enriched in peripheral sensory neurons. The voltage-dependence of the 4-AP block and the single binding site for this inhibitor are consistent with 4-AP binding in the pore of Deg/ENaC channels as it does Kv channels, suggesting a similar mechanism of inhibition in these two classes of channels. These findings argue that effects on both Kv and Deg/ENaC channels should be considered when evaluating the actions of 4-AP. Importantly, the current results are consistent with 4-AP influencing the symptoms of MS as well as the course of the disease because of inhibitory actions on Kv and ASIC channels, respectively.

When nerves fire to transmit signals sodium is pumped out of the nerve and potassium is pumped in making an electrical charge difference to the nerve cell. Blocking Potassium channels helps keep nerves firing and counteracts the effects of demyelination. Hence it can help with symptoms of MS. However this study suggests that in addition to effects on potassium channels that move potassium in and out of the cell, it suggests that Fampridine/Fampyra may also block other channels, that have been implicated in part of the problem in progression. Therefore, in addition to an improvement on walking it may have a positive effect on walking. This is good news, but the question is where is the proof that it has any of this beneficial activity? This is just conjecture and one could make an argument for other scenarios. Amiloride is a drug that inhibits ASIC1 and this will be tested in progressive MSers soon.

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  • Amiloride is an antiepileptic and most probably a neuroprotector, according to the small study published this month. Now, one of the drawbacks of Ampyridine is the risk of seizures. Would it be plausible to think that Famp. and Amiloride would have a synergistic effect ? (both being neuroprotector and one of them helping against a serious SE of the other)

    • cocktails of drugs have potential merits but they also have risks of side-effects. However as you have done you can build arguments for creating such cocktails. It is a shame that pharma does not seem to be that interested in the poly pill, Prof G spent years doing the rounds with just such an idea, no bites maybe it was not the right time.

  • This is what I have noticed on this blog: If the drug is something the scientists have been involved with and paid for by the pharma to consult on then they will big-up the hype factor and say it's a big step in terms of curing MS. However, if the drug in question was developed by another team and the Team G brigade was not paid to oversee it in any way, then such drugs are labelled unproven to benefit MSers.

    Fampradine is less risky than most of the crap you guys promote.

    • You are quite wrong in your assertions. All opinions are unbiased regardless of whether team G has been involved in the studies or not.
      End of.

    • "This what I has noticed"…simply put hogwash.

      We post on stuff that is relevant to our research sure, because if we want you to understand what we are doing then it is important that we give you the background work and also we need to put it in context.

      We post on other things that may be of interest to some of you. We appreciate that some people did them interesting some don't

      Is every thing great in the MS drug world..clearly no and yes I do have to bite my lip sometimes and yes sometimes we are gagged, but to suggest we are just evangelical about the stuff we do is way, way off the mark.

      What are we hyping? Prof G is involved with most MS drugs somewhere along the line, MD & MD2 seldom get consulting fees, so what every we say it is unlikely because we are getting paid. So on that point you are wrong.

      How many times have I said that drugs will cure MS? Not many please and it would invariably come with proviso. Please give examples

      I am afraid you may not know if we have not had any resource to look at fampridine or not?

      I do not believe that we have said anything negative about famyridine
      it clearly works for some people and improves their walking.

      The above post gives a theorectical framework that famyridine could be neuroprotective, just like BG-12 has a theorectical framework, however you could make the argument because the drug is allowing the nerves to work harder and because of its mechanism, it could cause nerve damage. I suspect not but it is a thorectical possibility
      Therefore we need to see the data to know one way or the other, is the data being collected that would give us an answer..I doubt it.

      The group from Oxford did the ASICS (above) stuff above, I do not remember being negative about this…oh but we may be involved in a trial which is UK based.

      I think you need to give us the evidence on what you theory is based.
      If you provide the evidence I will eat humble pie.

      p.s. To swedish sara I put a few flags in before posting.

    • Well I hope it helped..
      Anyway there's no need for you to defend yourselves.. this people aren't representing us.. As for being in the pocket of Big Pharma I wouldn't come here and educate myself if I thought that was the case. So take care
      Swedish Sara

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