Saturday, 14 March 2015

Symptomatic treatment effect of sodium channel blockers

Sodium channel blockers may be able to improve unsteadiness of gait in MSers. #MSBlog #MSResearch

"Nerves use sodium channels to conduct electrical signals. By allowing sodium to flow into the cell via sodium channels in a sequential fashion allows the cell membrane to conduct a electrical signal down an axon or nerve process. There are many different types of sodium channels. Some sodium channels open spontaneously and leak sodium; this affects the functioning of nerve cells. In MS certain neurons that are damaged by demyelination express different sodium channels; we call this aberrant expression. If these aberrant sodium channels leak sodium is causes that nerve cell to malfunction. This is what happens in the cerebellum or mini-brain that controls balance in MSers."
"In the study below the researchers show that blocking aberrant sodium channels (Nav1.8) with a new drug improves the functioning of the cerebellum. They use two different animal models; one that is engineered to express aberrant sodium channels and the other an animal model of MS called EAE. This is an exciting paper as it shows another potential use of sodium channel blockers in MS. We are currently exploring two different sodium channel blockers as neuroprotective therapies in MS. One study is looking at phenytoin in acute optic neuritis and the other oxcarbazepine as an add-on therapy in MSers with early SPMS (PROXIMUS TRIAL)."

Shields et al. Oral Administration of PF-01247324, a Subtype-Selective Nav1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis. PLoS One. 2015 Mar 6;10(3):e0119067. doi: 10.1371/journal.pone.0119067. eCollection 2015.

Background: Cerebellar symptoms significantly diminish quality of life in MSers. We previously showed that sodium channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.8 expression is linked to ataxia (unsteadiness of gait) and MS-like symptoms in mice. Furthermore, intracerebroventricular administration of the Nav1.8 blocker A-803467 temporarily reversed electrophysiological and behavioral manifestations of disease in a mouse MS model; unfortunately A-803467 is not orally bioavailable, diminishing the potential for translation to human patients. 


Objective: In the present study, we assessed the effect of per os (p.o.) dosing of a new orally bioavailable Nav1.8-selective blocker, PF-01247324, in transgenic mice expressing Nav1.8 in Purkinje neurons, and in wildtype mice in the experimental autoimmune encephalomyelitis (EAE) model. 

Methods: PF-01247324 was administered by oral gavage at 1000 mg/kg; control groups received an equal volume of vehicle. Behavioral assays of motor coordination, grip strength, and ataxia were performed. 

Results: We observed significant improvements in motor coordination and cerebellar-like symptoms in mice that received PF-01247324 compared to control littermates that received vehicle. 

Conclusion: These preclinical proof-of-concept data suggest that PF-01247324, its derivatives, or other Nav1.8-selective blockers merit further study for providing symptomatic therapy for cerebellar dysfunction in MS and related disorders.

9 comments:

  1. Prof G,

    Sodium channel blockers are referred to as a possibly add on therapy. What about those patients who have opted for an induction therapy. As a recipient of alemtuzumab i would still be interested (belt and braces approach) in a neuroprotective agent. Would such agents, if ey showed effectiveness, be available to me?

    ReplyDelete
    Replies
    1. With an induction therapy in my mind its even a better idea as a add on, because the induction therapy has gone so you are essentially only taking the neuroprotective drug. Drugs interact with each other to produce good and often unwanted effects so for some sodium channels blockers they cause the production of molecules in the liver that degrade drug.. I believe this is still classed as a add-on so I would say yes. I could be that if you start treatment early enough, this is not actually needed. Time will tell

      Delete
  2. Do MSers ever become 'Hypersexual' ongoing brain and spinal cord injury? (http://www.brainlinemilitary.org/content/multimedia.php?id=8361)

    I am being serious.

    ReplyDelete
  3. Would you still be able to use Ampyra?

    ReplyDelete
    Replies
    1. Maybe Fampyra/Ampyra has some neuro-protective benefits which have not yet been explored/trialled/documented??? I've just started on it and am keeping my fingers crossed that I'm one of the 35% who do respond to it. Oh bliss, oh joy - it would be so wonderful to be able to walk more than 150 metres without needing to rest...................

      Delete
    2. Same anon: glad you think so; I'd be concerned that blocking so much cell activity with both drugs would result in some nasty stuff long term. This is on top of my concerns about Ampyra itself.

      I've been on Ampyra for a while and I think it might be chemically habit forming in MSers who were super responders to it. (Not sure this is the right phrasing but it's clear when I miss a dose. The withdrawal kicks in within hours and I find myself immediately reaching for the bottle to relieve the spasms and pain.)

      Adding a different channel blocker on top sounds tempting because Ampyra clearly works, but I have many concerns about the method of this drug as is...

      Delete
    3. There are theoretical question marks but this needs a formal look I think

      Delete
  4. I have been on Ampyra for 4.5 years. People should look beyond the 25% as that was a limited timeframe. I could only walk a few feet and now walk a half mile, and everything is much faster. They didn't test handwriting. I was barely able to write and now have stronger hands and no problems. My grip strength is much better. For some reason, my MS has not progressed since being on Ampyra and there is no explanation.

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.