Monday, 16 July 2018

Remyelination. Is ivermectin the next great thing or something dangerous?

What do Remyelination, Parasites and Collie Dogs have in common?


Answer..A response to Ivermectin. 

This a drug that is used to kill parasites,such as head lice and parasitic worms and has been used by millions of humans and farm animals.

However, before runing off to the pet shop or doctor to get your fix of remyelination agent...please read this.

In a new study it is reported that ivermectin can induce microglia to exhibit anti-inflammatory effects and promote remyelination



DOI 10.15252/emmm.201708743| Published online 04.07.2018

EMBO Molecular Medicine (2018) e8743



Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen‐ or tissue damage‐induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. 

Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro‐inflammatory phenotype and inhibited myelin phagocytosis. Moreover, P2X4R blockade in microglia halted oligodendrocyte differentiation in vitro and remyelination after lysolecithin‐induced demyelination. 

Conversely, potentiation of P2X4R signaling by ivermectin (IVM) favored a switch in microglia to an anti‐inflammatory phenotype, potentiated myelin phagocytosis, promoted the remyelination response, and ameliorated clinical signs of EAE. Our results provide evidence that P2X4Rs modulate microglia/macrophage inflammatory responses and identify IVM as a potential candidate among currently used drugs to promote the repair of myelin damage.





P2X4 receptors have been implicated in susceptibility to MS and it has been suggested that P2X4 receptors control the fate and survival of activated microglia. (Vázquez-Villoldo N, Domercq M, Martín A, Llop J, Gómez-Vallejo V, Matute C. Glia. 2014; 62:171-84). I don't want to discuss this.



However, when I saw your emails asking me what I think of ivermectin, which is suggested to be a P2X4 modulator that makes microglia become anti-inflammatory and a remyelination agent. I thought don't do it, unless we know it is safe to do.



I have been banging-on about the importance of translatability of studies from animals to humans. Every study on animals should think how the work is relevant to human biology. 

This study does not mention much about ivermectin except to say it is "already used as an anti‐parasitic agent in humans will facilitate challenging this drug in clinical trials in that demyelinating disease". 

However, I am not sure you want to do a trial in MS. This is because ivermectin is neurotoxic and kills nerves if it gets in the brain. 

However, this effect is not a problem in most humans and animals because it is pumped out of the brain by a molecule called P-glycoprotein. So if it is actively pumped out of the brain, how is it going to target microglia in the brain? However saying that we showed that p-glycoprotein is lost in MS lesions so you will get a neurotoxic molecule into areas that you don't want it to go.

It must have got in the brain in these experiements I guess. 

However, it is not going to do this effectively. In this study they used C57BL/6 strain mice which have P-glycoprotein (ABC-B1). Lucky this wasn't done in MF-1 strain mice, as you may well of had a dead mouse. 

These mice share a feature with Collie Dogs in that they both lack P glycoprotein. This means they cannot exclude ivermectin from the brain and so exhibit neurotoxicity, if they have the drug

I was taking to some one at a cannabis conference once and they told me about a pot-grower ,who got neurological problems after spraying pot with avermectin (a homologue of ivermectin) to get rid of mites, which is a pest of pot. So my guess would be that this person was p-glycoprotein deficient and so got neurotoxicity. We'll never know.

Mitoxantrone is used in MS, but it is also neurotoxic (kills/hurts monkies when delivered intrathecally)  and is actively pumped out of the brain by breast cancer resistance protein-ABC-G2), but it is used to target immune cells in the peripheral circulation, so does not have to get into the brain to do its job.

Should Ivermectin be used as a remyelination agent?. 

It needs to be done in a carefully controlled situation if it is to be done at all..Don't start self-experimentation and risk neurotoxicity, just because a rodent researcher, who maybe hasn't thought about translatability, says so.

5 comments:

  1. The number of compounds found to be remyelinating and neuroprotective in mouse studies is incomprehensibly large. If you are looking at using ivermectin to protect your brain you are really scraping the bottom of the barrel.

    My opinion is that MS is an autoimmune disease. That means that the damage is caused by the immune system. If the underlying cause of the condition is properly treated it is not clear that there will be any need for neuroprotective therapies, although neurorestoration will be needed.

    That said, there exist already many proven, potent neuroprotective and neurotrophic compounds that one can access. HGH can be prescribed by any GP. Estradiol can, too. GLP-1 agonists like Liraglutide are easy to access. On the more experimental end, healing peptides like BPC-157, fibroblast growth factor 2 peptide mimetics and VEGF peptide mimetics can all be found if you know where to look. Telmisartan is good for the brain via several pathways. All of these are a better option than things like ivermectin, and even better than things like micanazole and anti histamines and all the other things claimed to be somewhat remyelinating.

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  2. Scraping the bottom of the barrel...I'm simply reporting on the paper

    "My opinion is that MS is an autoimmune disease"....Where is your proof? What is the autoantigen?...surely not myelin basic protein?

    If it is just autoimmune, why deso HSCT after immunoablation not halt MS in every one?

    I think the immune problems lead to a nervous problem that is autoimmune independent. This process trickles on for years after the immune insult and this aspect needs to be treated if you already have the condition.

    That said, there exist already many proven, potent neuroprotective and neurotrophic compounds that one can access......Not proven for MS. Everything you write is just wishfull thinking.

    However, why not put your pen where your mouth is and provide the details for
    the above agents into the request from the MS Society. This needs details and also pharmacological data, to suggest that a peptide is going to useful for something in the CNS is sort of wishful thinking. A peptide will last a few minutes in the circulation and probably wont get into the CNS. "BPC 157 will heal your body like Wolverine"....really it is not sold for human use.

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    Replies
    1. It's not autoimmune in the classical sense. It's not autoimmune like EAE. It's an aberrant immune response triggered by EBV infected B cells. It involves B cells, the innate immune system and some T cells. We don't understand the immune system well enough to understand the nature of that inflammatory immune response, but I think underlying the damage is caused by the immune system. MS is a disease that strikes healthy young people. It's not a neurodegenerative condition like Alzheimers or ALS. It almost never strikes elderly individuals. I cannot see any proposed mechanism behind a primary neurodegenerative theory of MS. It is clearly a low grade aberrant immune mediated condition. I think there is some validity in repeated insult eventually triggering some level of neurodegeneration independent of the insult, but I still think low grade inflammation is a big part of SPMS and PPMS.

      Googling BPC-157 will bring you to stupid sites like the one you quoted a line from. I suggest you search "BPC-157" on pubmed. The production patent compiled a vast amount of literature on its effects, check it out: https://patents.google.com/patent/WO2014142764A1/en

      Also, the half-life is about 4 hours. That means 3 easy sub-q injections per day for full coverage. Peptides obviously are susceptible to protelytic disposal but that doesn't mean their half-lives are always minutes. In mice studies there is good evidence of penetrance into the CNS. I think you'd be more on the fringe today if you claimed most small peptides don't meaningfully penetrate the CNS, especially endogenous peptides like BPC-157.

      All the other agents I listed have good evidence supporting their use for MS. Check out the VEGF mimetic peptide QK. You always write about repurposing failed anti-stroke therapies that weren't able to be administered fast enough. The evidence supporting QK for stroke is strong (and it's stronger for BPC-157).

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  3. "not halt MS in every one?"

    I dont know of a drug/treamnet with a 100% efficacy

    Do you?

    :)

    Obrigado

    ReplyDelete

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