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

Alazne Zabala, Nuria Vazquez‐Villoldo, Björn Rissiek, Jon Gejo, Abraham Martin, Aitor Palomino, Alberto Perez‐Samartín, Krishna R Pulagam, Marco Lukowiak, Estibaliz Capetillo‐Zarate, Jordi Llop, Tim Magnus, Friedrich Koch‐Nolte, Francois Rassendren, Carlos Matute, María Domercq. P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis

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.

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