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Tuesday, 12 August 2014

Immunomodulatory Therapy in Autism - Potassium Channel Kv1.3, Parasitic Worms, and their ShK–related peptides



Regular readers of this post will know that I believe that Immunomodulatory therapy has great promise for treating various subtypes of autism.  In effect, I want to bring the over-activated immune system back under control.  Two methods that appeal are:-

·        The steroid, Prednisone, because it is cheap and though it has side effects, they are very well understood. It also has been shown to be effective in autism and related conditions like PANDAS and Landau-Kleffner syndrome (LKS)

·        Parasitic worms appeal because they are known to have beneficial effect in many auto-immune conditions ranging from arthritis to autism, but nobody really understood why.  Until now.

This post is about the worms and recent research which has established that it is likely that they work by blocking the potassium channel Kv1.3.

You will have noted that this blog keeps going on about ion channel dysfunctions and autism.  We already know that Cl-, Ca2+ , K+ and Na2+ are all implicated.

When researching calcium channel blockers for autism, one reason I picked Verapamil was that it is also a potassium channel blocker.  My earlier experiments have shown that hypokalemic sensory overload exists in autism, I showed that oral potassium could treat sensory overload.

Hypokalemic Autistic Sensory Overload

 
This blog is (slowly) working its way through the ion channel dysfunctions known to exist in autism.

Well, it appears that Verapamil also blocks Kv1.3.

Block of the lymphocyte K+ channel mKv1.3 by the phenylalkylamine verapamil



Research Down Under

Researchers in Australia have identified the chemicals released by parasitic worms that have the effect of subduing the immune system.  They identified a large family of Stichodactyla helianthus toxin (ShK)–related peptides in parasitic worms, they showed that these peptides acted to inhibit Kv1.3 channels in human T cells.


Abstract

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)–related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar–micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7 effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases

A less heavy summary is here:-

'Wormpill' could ease autoimmune disease symptoms

  
The researchers noted that Kv1.3 is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases.

So it seems that they have identified the mechanism of action of the worms.

Earlier posts have mentioned intentionally swallowing TSO parasites (Helminthic therapy) for autism and the trials now ongoing by Coronado Biosciences.   Here is part of one post:-

I think that TSO is very interesting.  It is now being developed by Coronado Biosciences as a therapy for several inflammatory conditions including:-

·        Crohn’s disease
·        Ulcerative Colitis
·        Autism

Here is a link to all the clinical trials they are running.

The idea behind TSO is that the parasites have evolved a method of ensuring their survival in their host, by subduing the immune system, so that they are not killed/ejected.  By down-regulating the immune system, they become a therapy for diseases featuring an over active immune system.

This all started a few years ago when one autism Dad figured all this out and tried it on his own son.  Then began the long process of clinical trials, which then ended up with Coronado Biosciences.  The Dad’s website is here.

The Australians have the idea of making their (ShK)–related peptides into a drug therapy.  So no need to swallow those worms after all.


Verapamil or Stichodactyla helianthus toxin (ShK)–related Peptides

Just as the Australians may have trumped Coronado Bioscience with their better-than-a-worm peptide pill, has Verapamil the ability to trump the Ozzies?

We know that Verapamil is neutralizing many allergic reactions affecting autism all over the body.  This appears to be a combination of mast cell stabilization and a possible effect on pancreatic function that reduces GI problems.  But is Verapamil’s inhibitory effect on Kv1.3 also providing a broader immunomodulatory effect as well?  It does indeed look possible.

We would need somebody using TSO worms for autism, to see if Verapamil was effective for them too.  Any volunteers?

Unlike the TSO worms and the ShK peptides, Verapamil is cheap and sitting on the shelf in your local pharmacy.





6 comments:

  1. Thank you for your blog! I stumbled upon it about a year ago looking into ion channels and have to say it is at the top of my dean’s list for autism blogs.

    I have a few questions I’ve gathered over the past year if you have time to answer

    1) Another blog I follow is the work of Dr. Manuel Casanova. I wonder if you have read his research and if so what your thoughts are on his mini columns theory and using rTMS to address sensory sensitivities?

    http://corticalchauvinism.com/

    2) The first drug you gave your son was Bumetanide. Do you think if you had given him the Clonazepam first he would have reacted negatively since it increases GABA and the Bumetanide is needed to turn GABA inhibitory? I ask because my ASD/ADHD son was put on Depakote (valproic acid) and instead of becoming calm, mood stabilized and fatigued he had the exact opposite reaction. Could this be because his GABA is Thank you for your blog! I stumbled upon it about a year ago looking into ion channels and have to say it is at the top of my dean’s list for autism blogs.

    I have a few questions I’ve gathered over the past year if you have time to answer

    1) Another blog I follow is the work of Dr. Manuel Casanova. I wonder if you have read his research and if so what your thoughts are on his mini columns theory and using rTMS to address sensory sensitivities?

    http://corticalchauvinism.com/

    2) The first drug you gave your son was bumetanide. Do you think if you had given him the Clonazepam first he would have reacted negatively since it increases GABA and the bumetanide is needed to turn GABA inhibitory? I ask because my ASD/ADHD son was put on Depakote (valproic acid) and instead of becoming calm, mood stabilized and fatigued he had the exact opposite reaction. Could this be because his GABA is excitatory?

    3) In this post you write:

    When researching calcium channel blockers for autism, one reason I picked Verapamil was that it is also a potassium channel blocker. My earlier experiments have shown that hypokalemic sensory overload exists in autism, I showed that oral potassium could treat sensory overload.

    Does a potassium channel blocker work to treat sensory overload? I understand the immunity/T cell angle but I’m not understanding what a blocker does vs. supplementing with potassium.

    My son has ASD/ADHD, asthma,allergies and perhaps epileptical activity. I’ve done the whole nutrigenomics road (including potassium/magnesium) which helped somewhat.

    At this point I’m really looking to solve his sensory overload. It is the biggest thing that keeps him from being able to attend in school/life and be able to engage in socializing.

    I’m working on trying to find a doctor who will back the bumetanide.

    Again thank you so much for your insights!?

    3) In this post you write:

    When researching calcium channel blockers for autism, one reason I picked Verapamil was that it is also a potassium channel blocker. My earlier experiments have shown that hypokalemic sensory overload exists in autism, I showed that oral potassium could treat sensory overload.

    Does a potassium channel blocker work to treat sensory overload? I understand the immunity/T cell angle but I’m not understanding what a blocker does vs. supplementing with potassium.

    My son has ASD/ADHD, asthma,allergies and perhaps epileptical activity. I’ve done the whole nutrigenomics road (including potassium/magnesium) which helped somewhat.

    At this point I’m really looking to solve his sensory overload. It is the biggest thing that keeps him from being able to attend in school/life and be able to engage in socializing. He does great one on one in his preferred environment but beyond that we start to lose him.

    I’m working on trying to find a doctor who will back the bumetanide.

    Again thank you so much for your insights!

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    Replies
    1. I have read some posts by Dr. Manuel Casanova and in particular his comments that much analysis from brain bank samples may be flawed. He questions the knowledge of the researchers and the integrity of their samples.

      I have not read about using rTMS to address sensory sensitivities, but I will look into it.


      Bumetanide is shifting the balance from excitatory to inhibitory in how GABA behaves. In very low doses, Clonazepam is claimed to do something similar, but this time via a sodium channel rather than a chloride transporter in the case of bumetanide. At the normal dose, which is 10 to 100 times higher, the effect of Clonazepam is something entirely different. In high doses Clonazepam is an anti-anxiety and anti-epileptic drug. In my use, the smallest existing tablet (0.5 mg) is given in tiny doses over 10 days. I was very surprised that such a small dose had any effect, but as in the trials on mice, it really dose work. I rather expected that since I already gave bumetanide, there would be no further effect.

      So to answer your question, I think very low doses of Clonazepam would be effective without Bumetanide.

      Valproic acid is thought to work by increasing the amount of GABA, rather than modifying the effect of GABA. I think that many such drugs may have the opposite effect to that intended, your son did not need more GABA, indeed maybe he needed less, or maybe he just needed to “re-tune” GABA. I also doubt that GABA has just one axis, excitatory to inhibitory, I think it might have several, all of which need to be tuned to make the brain function optimally. It would seem that both Bumetanide and Clonazepam in effect tune GABA, but they seem to be complementary, they are not alternatives.

      The disadvantage of Clonazepam is that it is a little hard to find the effective dosage. Both slightly higher and slightly lower doses will have no effect. Due to the long half-life, it will take about 5 days to reach a steady level in the body.

      Bumetanide needs a certain dosage to take effect and higher doses have no additional impact.

      I had one person with Asperger’s tell me that Baclofen make him feel much better. This is affecting GABA in yet another way.


      Potassium itself will affect potassium channels and a potassium channel blocker will also increase the level of potassium in the blood. I read about hypokalemic sensory overload and hypokalemic periodic paralysis. In both cases, oral potassium almost immediately overcomes the symptoms. So I did a little experiment to see the effect on both my sons. I measured how loud they could listen to a recording of a baby crying. In my NT son, drinking oral potassium had no impact, in my son with ASD, he could tolerate this sound at a much higher volume having taken the potassium.

      So I think that there is a potassium channelopathy at the route of the sensory problem in autism.

      You can try this out at home and see if it works for your son. Eating bananas was not as effective as oral potassium.

      If asthma and allergies are present, then Verapamil might very well be helpful, but your doctor might take some convincing.

      Delete
  2. Ponstan - have you seen it being used effectively for calming purposes in autism and if so - why could it work? My sons react very well to ponstan but panado doesnt seem to work as well, if at all. They seem to often be in some kind of discomfort and the ponstan seems to soothe the pain or discomfort better than panado or neurofen.

    ReplyDelete
    Replies
    1. Max, Ponstan is very interesting but most people cannot obtain it. Ponstan, like all NSAIDs such iubprofen, will reduce an inflammatory substance called IL-6. IL-6 makes autism worse and so anything that increases IL-6 from allergy to juvenile arthritis will cause a problem.

      Paracetamol is not good for people with autism because one side effect is depleting the body's main antioxidant called GSH. So ibuprofen or ponstan is the choice for people with autism.

      One researcher wrote to me to highlight an effect exclusive to Ponstan, which may be what you are seeing. It is very complex.

      Ponstan is suggested to be useful to affect the ion channels expressed by the genes ANO 2/4/7 & KCNMA1, which appear to be often dysfunctional in autism. We saw in this post

      http://epiphanyasd.blogspot.com/2015/12/autism-treatments-proposed-by-clinical.html

      the researcher,Knut, highlighted that Fenamates act as CaCC inhibitors and also stimulate BKCa channel activity. Ponstan is a Fenamate.

      I would suggest you see if ibuprofen is as good as ponstan. If Ponstan is much better, your kids may have a dysfunction in the genes ANO 2/4/7 or KCNMA1.

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    2. Wow! Thank you so much for this! I never expected something ao profound - just saw my boys doing much better on Ponstan than Panado and could not figure out why ... thought they had constant pain and the Ponstan may helped relieve it you know? Thank you so much - please keep posting!

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  3. Instead of Prednisone try sulforaphane: http://evgen.com/about/
    http://www.hopkinsmedicine.org/news/media/releases/brain_inflammation_a_hallmark_of_autism_large_scale_analysis_shows

    ReplyDelete

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