Axonal Degeneration & Sodium Density

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Axonal Degeneration & Sodium Density

Postby OddDuck » Tue Dec 07, 2004 5:48 am

Here's a fairly recent article (from Yale University, so I believe it could be thought of as highly credible) that again connects maintaining sodium density with preventing axonal degeneration (axonal degeneration has been found to be what produces permanent disability in MS). I have posted other findings and postulated on regulation of ion sodium channel density in previous threads and discussions. I touched upon the role of Na(v) before, also.

The mention within this article of tetrodotoxin (which is a highly toxic substance found in puffer fish), is not indicative of a direct treatment for MS, though. I quote from http://www.chm.bris.ac.uk/motm/ttx/ttx.htm:


A single milligram or less of TTX - an amount that can be placed on the head of a pin, is enough to kill an adult.


Its use in this research was simply as an agent for producing desired results as it pertained to sodium density, but not as a treatment source.

Anyway, there is other research going on regarding treatment agents to help maintain sodium density, but I won't go into those links right now.

I thought this might be an interesting article for some folks here, as we have recently shared theories regarding ion channels, sodium density, and axonal degeneration in MS.

I'd like to point out again, how important the migration of microglia and macrophages in MS appears to be, and how inhibiting that activation appears to be highly beneficial.

Deb


**************************************

Glia. 2005 Jan 15;49(2):220-9. Related Articles, Links

Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.

Craner MJ, Damarjian TG, Liu S, Hains BC, Lo AC, Black JA, Newcombe J, Cuzner ML, Waxman SG.

Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, Connecticut.

Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal sodium channels can trigger axonal degeneration, recent studies have tested sodium channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, sodium channel blockers may also interfere with inflammatory mechanisms. We therefore examined the novel hypothesis that sodium channels contribute to activation of microglia and macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of sodium channel Na(v)1.6 expression in activated microglia and macrophages in EAE and MS. We further demonstrate that treatment with the sodium channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%. Supporting a role for sodium channels in microglial activation, we show that tetrodotoxin, a specific sodium channel blocker, reduces the phagocytic function of activated rat microglia by 40%. To further confirm a role of Na(v)1.6 in microglial activation, we examined the phagocytic capacity of microglia from med mice, which lack Na(v)1.6 channels, and show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice. Our findings indicate that sodium channels are important for activation and phagocytosis of microglia and macrophages in EAE and MS and suggest that, in addition to a direct neuroprotective effect on axons, sodium channel blockade may ameliorate neuroinflammatory disorders via anti-inflammatory mechanisms. (c) 2004 Wiley-Liss, Inc.

PMID: 15390090 [PubMed - in process]
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Postby raven » Tue Dec 07, 2004 10:27 am

O.K. As there isn't a fugu restaurant close by, I'll see your puffer fish and raise you another AED :wink:

Phenytoin is sometimes prescribed for neuropathic pain in MS but it may have further beneficial effects.

Department of Neurology and Paralyzed Veterans Association/Eastern Paralyzed Veterans Association of America Neuroscience Research Center, Yale University School of Medicine, New Haven, CT 06510, USA.

Axonal degeneration within the spinal cord contributes substantially to neurological disability in multiple sclerosis (MS). Thus neuroprotective therapies that preserve axons, so that they maintain their integrity and continue to function, might be expected to result in improved neurological outcome. Sodium channels are known to provide a route for sodium influx that can drive calcium influx, via reverse operation of the Na+/Ca2+ exchanger, after injury to axons within the CNS, and sodium channel blockers have been shown to protect CNS axons from degeneration after experimental anoxic, traumatic, and nitric oxide (NO)-induced injury. In this study, we asked whether phenytoin, which is known to block sodium channels, can protect spinal cord axons from degeneration in mice with experimental allergic encephalomyelitis (EAE), which display substantial axonal degeneration and clinical paralysis. We demonstrate that the loss of dorsal corticospinal tract (63%) and dorsal column (cuneate fasciculus; 43%) axons in EAE is significantly ameliorated (corticospinal tract: 28%; cuneate fasciculus: 17%) by treatment with phenytoin. Spinal cord compound action potentials (CAP) were significantly attenuated in untreated EAE, whereas spinal cords from phenytoin-treated EAE had robust CAPs, similar to those from phenytoin-treated control mice. Clinical scores in phenytoin-treated EAE at 28 days were significantly improved (1.5, i.e., minor righting reflex abnormalities) compared with untreated EAE (3.8, i.e., near-complete hindlimb paralysis). Our results demonstrate that phenytoin has a protective effect in vivo on spinal cord axons, preventing their degeneration, maintaining their ability to conduct action potentials, and improving clinical status in a model of neuroinflammation.


Yet more indication that the sodium channel plays an important role in axonal degeneration.

Robin
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Postby OddDuck » Tue Dec 07, 2004 12:05 pm

:lol: (I thought you were taking a nap, Robin.)

Yep............less calcium, more sodium. (Speaking ionically, that is.) hehehe.........

:wink:

Deb

EDIT: Oh, yea..........I'll just raise you a Keppra.
Last edited by OddDuck on Tue Dec 07, 2004 12:06 pm, edited 1 time in total.
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Postby Daunted » Tue Dec 07, 2004 12:06 pm

This is all SO over my head- but I thought I would mention that I had seen at least one doctor theorizing that Aimspro works on the 'sodium channel', (whatever that is!).
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Postby OddDuck » Tue Dec 07, 2004 12:11 pm

Oh, and by the way, there IS a good Japanese restaurant in downtown Nashville, Robin. :wink:

Deb
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Postby raven » Tue Dec 07, 2004 12:35 pm

Komban-wa Deb, o-genki deska? :)

Daunted, I've also seen that theory. Improved neural conduction through mdification of the sodium channel would explain the reported 'sudden' effects of Aimspro. Unfortunately there is no scientific information available on Aimspro so it's all guesswork and anecdotal until Daval see fit to release proper data.

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Postby OddDuck » Tue Dec 07, 2004 12:47 pm

Robin......... Tanoshin-deru? :wink: (Learn that in karate class, did ya? hehehe....)

And I'll still stick with the tried and true desipramine and levetiracetam to maintain my sodium density and inhibit calcium influx. :wink:

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Postby Sharon » Tue Dec 07, 2004 4:24 pm

Accorda Therapeutics are conducting a trial on Fampridine-SR - following is a quote from their website:

Researchers have shown that, contrary to popular belief, most people with spinal cord injury (SCI) do not have severed cords; rather, most have blunt damage to the cord. The great majority of such individuals have some axons within the spinal cord that survive the injury. However, these surviving axons often are damaged and lose part of their myelin, the insulating sheath that permits electrical impulses to be conducted down the axon. Nerve impulses "short circuit" in demyelinated axons, much like electricity in a wire whose insulation is stripped. Thus, even though a demyelinated axon is alive, it cannot transmit motor or sensory impulses. In multiple sclerosis (MS), the myelin is believed to be damaged by the body's own immune system, rather than by physical trauma as in SCI.

Fampridine-SR's major action is to block specialized potassium channels on axons. When an axon is demyelinated after injury, large numbers of these potassium channels are exposed and "leak" potassium ions, causing the axon to "short circuit".

By closing the exposed potassium channels, Fampridine-SR permits the axon to transmit impulses again, even in a demyelinated state.


Since I am still learning and on the "ground floor of MS technical knowledge" so to speak, I am not sure if this relates to the sodium you all have been talking about (I am relating to chemistry class - potassium and sodium always seemed to go together) There are current trials running on the use of Fampridine and I believe the results should be released in 2005. Phase Two trials did show improvement for MS'ers.

Sharon
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Postby raven » Wed Dec 08, 2004 12:44 am

Sharon,
Yes, the interaction between sodium / potassium ions and the axon create the electrical impulse or action potential that is the nerve signal.

Robin.
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Postby Daunted » Wed Dec 08, 2004 10:32 am

Isn't this 4-AP (or something like that) that you can actually get from some compounding pharmacies?

I've thought of trying it since leg weakness is my primary symptom.
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Postby raven » Wed Dec 08, 2004 11:00 am

If the 4-AP you are referring to is 4-aminopyridine then I would be cautious. 4-AP is a broad spectrum potassium antagonist which appears to have detrimental effects upon oligodendrocytes and remyelination.

K+ channel blockade impairs remyelination in the cuprizone model.

Bacia A, Wollmann R, Soliven B.

Department of Neurology and Committee on Neurobiology, Brain Research Institute, University of Chicago, Chicago, Illinois 60637, USA.

The adult CNS has the capacity to remyelinate following metabolic, toxic and autoimmune demyelinating insults. In cuprizone-induced demyelination, spontaneous remyelination occurs after the cessation of cuprizone diet. We used the cuprizone model to investigate the role of glial K(+) channels in oligodendroglial (OLG) regeneration and remyelination in vivo. We found that treatment with 4-aminopyridine (4-AP), a broad-spectrum K(+) channel antagonist, results in: (1) decreased number of oligodendroglial progenitors (OP) and OLGs; (2) diminished astrogliosis; and (3) decreased remyelination in the corpus callosum based on the immunoreactivity to myelin basic protein (MBP), Rip monoclonal antibody, and by electron microscopy. Our findings support the concept that glial K(+) channels play an important role during OLG regeneration and remyelination, a crucial factor to be considered during the development of therapeutic strategies to facilitate recovery in demyelinating diseases and spinal cord injury.

PMID: 15378653 [PubMed - in process]


Have you tried resistance exercises to help with your weakness? I have found that exercise has been very helpful to me.

Robin
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Postby Sharon » Wed Dec 08, 2004 11:45 am

Daunted -

Raven mentioned exercise - I could not agree more. I have been participating in a research exercise program for MS'ers. I had a follow-up visit yesterday and will be posting about my experience when I get a few extra minutes. It has been a very rewarding and positive program - I would hope that more MS'ers would have the same opportunity in the future.

Sharon

Oops, it was Robin, not Raven
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Postby raven » Wed Dec 08, 2004 12:08 pm

Hi Sharon,

When you have time I would be very interested in hearing your exercise regime and experiences. Having recently started an exercise program any hints and tips would be more than welcome.

Robin / Raven..... Guess I wasn't very good at hiding behind my secret superhero identity! :lol:
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Postby Sharon » Thu Dec 09, 2004 7:55 am

Robin -

I just posted information on the exercise study in the General Discussion forum under the topic "Research on Exercise". My suggestion to you is to go to the websites - read and also watch the video on the IsoPump machine. Then, get back to me with any of your questions - I am sure you will have some. Hopefully, by the end of the study there will be a protocol exercise program which one could mimic in their home. The IsoPump machine is in development , has not been commercialized; therefore, you cannot find one at your local health club.

An idea would be to take the info you get from the website to your local health club and ask them to help you mimic the type of exercise. The positioning of the body on the leg press ( -6 degrees below horizontal) is very important and holding your breath. My understanding is that you are "backforcing" fluids into tissues which are then nourished.

The doctor who developed the study, is looking for more funding from the government to continue the study. If you are close to one of the study sites, I would encourage you to find out more information. It has been a very positive experience for me.
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Postby carolsue » Mon Dec 10, 2007 6:30 pm

Picking this thread up because I have to consider going on meds to lower blood pressure. Apparently, one category of meds are calcium channel blockers. It would seem that I might derive some neuroprotection if I chose a calcium blocker. OddDuck, or Raven, care to comment?

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