Chronic Microglial Activation in ME/CFS, And Its Possible Treatment Using Microglial Inhibitors

[alex3619]

Thank you @Hip for an interesting summation. I think I can add a few points.

Many of the supplements have benefits other than to do with microglia. It could be hard to sort out what is microglia related and what might be related to other effects.


Many of us have extremely low vitamin E. That would be a great place to start.

Silymarin is problematic if you have haemochromatosis or a tendency to it. Otherwise it has very good detox potential.

I use sesame seed oil a lot when I cook Asian dishes. I have never noticed any benefit, though to be fair I was not looking for one.

Resveratrol I use a lot. I don't need it every day, but I took some last night. I will say more on implications of mechanisms later.

Magnesium has benefits all by itself, and might have a positive impact on excessive NMDA activation.


I have long been intrigued by a potential LPS link. High serum LPS has been found in patients a number of times. This is begging for a well funded large study. I planned to write a blog on this two years ago and then my brain crashed. I am still trying to recover even the cognitive capacity I had two years ago. I think LPS might be important.


Wasn't interferon gamma listed as being high in ME by the NCNED research group at Griffith University?


While there may be a leptin link, it could be association and not causation. Leptin is likely to correlate with other factors.

Though note that very little LPS passes through an intact blood-brain barrier.1

I don't know if this matters much. LPS sends the immune system into crisis mode, and can even trigger immune cell migration. Those cells can release cytokines when passing through the brain, and these might cross the blood brain barrier.


Not just antioxidant effects have a variable dose dependent response. I suspect resveratrol does. I know pycnogenol does ... at one dose it can lower NO, and at another raise it. I forget the details. Many of these substances might induce variable response depending on dose and cofactors.


I have lots more to say, about combining these things and the COX2-ischemia link, as well as what I figured out from resveratrol. I hope to write about these later.

 

[nandixon]

Perhaps another possibility mentioned by a doctor/researcher (Jan M Keppel Hesselink · Instituut voor Neuropathische Pijn) here:
http://www.researchgate.net/post/Microglia_and_minocycline

You should look into palmitoylethanolamide, a lipid signaling PPAR alpha agonist, which clearly inhibits overactive glia cells and mast cells. WE use it frequently in neuropathic pains and it has a very impressive effect in some patients.

Jul 23, 2013

Has anyone tried palmitoylethanolamide (PEA)?

Edit: I see that Cort talks about this here:
http://www.cortjohnson.org/blog/201...-fibromyalgia-chronic-fatigue-syndrome-mecfs/

Dr. Younger included PEA in his long list of potential microglial inhibitors that might be of use in Chronic Fatigue Syndrome and Fibromyalgia.

 

[Gondwanaland]

@Hip have you considered that you crashed due to physical and social exertion themselves as Kimsie suggests on another thread?

 

[Hip]

@Gondwanaland
It's possible. What I am going to do is repeat the same experiment quite soon, taking the same set of supplements once again, but this time I will not overexert myself.

 

[Ema]

Has anyone tried palmitoylethanolamide (PEA)?

I just ordered some...I'll keep you all posted once I have a chance to give it a try!

 

[Hip]

I see that Cort talks about this here:
http://www.cortjohnson.org/blog/201...-fibromyalgia-chronic-fatigue-syndrome-mecfs/

Dr. Younger included PEA in his long list of potential microglial inhibitors that might be of use in Chronic Fatigue Syndrome and Fibromyalgia.

I could not find any studies that demonstrate palmitoylethanolamide (PEA) inhibits microglia activation. Does anyone have any links to such studies?

 

[Ema]

I think the study being referenced is this one indicating that PEA can normalize microglial cells after formalin.

It's a little suspect though as one of the authors has interest in a company that makes a PEA supplement.

http://www.ncbi.nlm.nih.gov/m/pubmed/23394524/

 

[Hip]

@Ema
Thanks for the link. I see the authors of that study say "We found that formalin induced a significant microglia and glia activation normalized by PEA". Which I presume is a slightly confusing way of saying that PEA inhibited formalin-induced microglial activation.

I have not heard of formalin (= formaldehyde dissolved in water) being used to induce microglial activation though. In all the other studies on microglial activation inhibitors I have seen, they either used LPS or interferon gamma to trigger microglial activation.

 

[Ema]

There is a book that I can't link to from my phone called Purinergic Signaling and the Nervous System that talks about formalin induced activation of microglial cells.

It also mentions that an old drug called suramin can block this. So then I found this article that talks about trials of suramin in autistic children. Seems to be quite a few parallels with ME/CFS though suramin doesn't look like the magic pill either due to side effects.

http://www.science20.com/news_artic...n_reverses_autismlike_symptoms_in_mice-138739

 

[nandixon]

@Hip
When I do this search:
"palmitoylethanolamide AND (microglia OR microglial)"
on PubMed, I get 18 results, of which more than a third (including several review articles) in one way or another refer to the ability of PEA to downregulate microglia, including the article @Ema found.
Edited to add this link:
http://www.ncbi.nlm.nih.gov/pubmed/?term=palmitoylethanolamide+AND+(microglia+OR+microglial)

[Just to note that, according to Hesselink, most of the research (including some 30 clinical trials) with PEA is appararently to be found in Italian journals.]

 

[Ema]

n all the other studies on microglial activation inhibitors I have seen, they either used LPS or interferon gamma to trigger microglial activation.

It just struck me as odd that LDN increases interferon gamma but also is supposed to inhibit microglial activation. Wonder how that works?

 

[Hip]

@nandixon
Looking at the abstracts of those 18 papers, only the study cited by Ema refers to PEA's ability to inhibit microglial activation. I have not looked through the full papers though.

It just struck me as odd that LDN increases interferon gamma but also is supposed to inhibit microglial activation. Wonder how that works?

LDN is thought to block the TLR-4 receptor on microglia, thereby inhibiting their activation. I guess that inhibitory effect via TLR-4 may be stronger than any activating effect via interferon gamma.

A comprehensive list of microglial activating substances is found on page 947 of this document:
Regulating Factors for Microglial Activation, by Yoichi Nakamura.

 

[nandixon]

@nandixon
Looking at the abstracts of those 18 papers, only the study cited by Ema refers to PEA's ability to inhibit microglial activation. I have not looked through the full papers though.

Just the ones referring to it in their abstracts:

#3 "The discovery that palmitoylethanolamide, a member of the N-acylethanolamine family which is produced from the lipid bilayer on-demand, is capable of exerting anti-allodynic and anti-hyperalgesic effects by down-modulating both microglial and mast cell activity has led to the application of this fatty acid amide in several clinical studies of neuropathic pain, with beneficial outcome and no indication of adverse effects at pharmacological doses."
http://www.ncbi.nlm.nih.gov/pubmed/24178954

#6 (@Ema's reference)
http://www.ncbi.nlm.nih.gov/pubmed/23394524

#7 "PEA delayed mast cell recruitment, protected mast cells against degranulation and abolished the nerve growth factor increase in sciatic nerve concomitantly preserving the nerve from degeneration, while reducing microglia activation in the spinal cord."
http://www.ncbi.nlm.nih.gov/pubmed/23394519

#10 "Conceivably, the action of palmitoylethanolamide could result, in part, from its ability to dampen mast cell and microglia activation."
http://www.ncbi.nlm.nih.gov/pubmed/22998138

#11 "Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100β overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS- positive cells in the substantia nigra."
http://www.ncbi.nlm.nih.gov/pubmed/22912680

#14 "Moreover, PEA treatment significantly reduced the activation of microglia and astrocytes expressing cannabinoid CB(2) receptor after SCI."
http://www.ncbi.nlm.nih.gov/pubmed/21354467

#15 "Here we show that PEA (0.001-1 μM) and the synthetic peroxisome proliferator-activated receptor (PPAR)-alpha agonist 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (Wy-14,643; 0.1-1 μM) reduced the number of microglial cells and protected dentate gyrus granule cells in excitotoxically lesioned organotypic hippocampal slice cultures (OHSCs)."
http://www.ncbi.nlm.nih.gov/pubmed/20221904

(Plus others...)

 

[Hip]

@nandixon
Thanks very much for copying out those quotes. You are quite right: several of those studies do provide evidence for PEA reducing microglial activation (I don't know why I missed them when I looked at these abstracts yesterday).

In their experimental models, studies #7, #11, #14 and #15 provide evidence for PEA's microglial activation-inhibiting effects. (Though studies #6 and #10 just mention or speculate about PEA's ability to reduce microglial activation, rather than providing evidence for it).

Note however that in the experimental models used in these studies, the methods employed to induce microglial activation were:
• Nerve compression injury (in studies #7 and #14);
• MPTP-induced injury (in #11) — MPTP is a standard way to model Parkinson's disease;
• Excitotoxicity-induced injury (in #15).

I am not quite sure how much these types of triggers of microglial activation apply to ME/CFS.

My hunch is that for creating experimental models or studies of ME/CFS, the most appropriate trigger of microglial activation might be interferon gamma. This is because interferon gamma is a Th1 cytokine, which appears during the antiviral immune response, and in virally-associated ME/CFS, you might expect interferon gamma to trigger the activation of microglia.

If you had say an enterovirus infection of the brain, for example (which some postmortem studies have shown occurs in ME/CFS), I presume (but I don't really know) that it would be interferon gamma secretion which triggers the activation of microglia in order to fight the infection. Having said that, interferon gamma is not one of the cytokines that is found elevated in the cerebrospinal fluid of ME/CFS patients, as far as I am aware.

A few of the studies cited at the beginning of this thread used models based on interferon gamma-induced microglial activation. But many of these studies used models based on LPS-induced microglial activation. Possibly this LPS model might be appropriate for diseases linked to chronic bacteria infection. And it might apply to some ME/CFS patients if the LPS from Gram negative bacteria in their guts translocates into the bloodstream, which is thought may happen in cases of leaky gut.

Infections and inflammation in the peripheries of the body (such as the gut) are also known to remotely activate microglia, via signaling to the brain along the vagus or trigeminal nerves. This is the sickness behavior response, which is the basis of Michael VanElzakker's vagus nerve infection theory of ME/CFS.



What we need to know is whether supplements/drugs that reduce microglial activation from one trigger (such as interferon gamma, LPS, MPTP, nerve injury, formalin) will also reduce the microglial activation induced by other triggers.

It would also be good to know what factor or factors cause the microglial activation found in ME/CFS.

I have added PEA to the list of microglial activation inhibitors at the beginning of this thread — many thanks.

 

[NK17]

Perhaps another possibility mentioned by a doctor/researcher (Jan M Keppel Hesselink · Instituut voor Neuropathische Pijn) here:
http://www.researchgate.net/post/Microglia_and_minocycline

Has anyone tried palmitoylethanolamide (PEA)?

Edit: I see that Cort talks about this here:
http://www.cortjohnson.org/blog/201...-fibromyalgia-chronic-fatigue-syndrome-mecfs/

I've taken Normast (PEA) this past summer apparently with no real benefit.
To be honest it's not easy to tease out any beneficial effect if you're taking different and several supplements and drugs at the same time.
I'll resume taking PEA soon and hopefully will report some good news.

 

[OverTheHills]

Just like to thank @Hip for this thread.

I have had a lot of benefit from LDN over the last couple of years, mainly on my sleep - went from dreadful quality, completely unrefreshing to good if broken (awake for 2 hours 3-5 am every night). Also reduced aches and pains.

After reading the list at the beginning of the thread I decided to start NAC (n acetyl cysteine) about 3 weeks ago which seems to complement the LDN. I have now halved my LDN use (too sleepy otherwise) and my sleep is more-or-less unbroken now. Which is great.

I'll give things a while longer to settle then see trial some others on the list and see whether I can fix anything else.

Proper sleep is lovely.

OTH

 

[Hip]

@OverTheHills
Glad you are getting benefits. Though bear in mind it's possible the benefits from NAC might be due to something other than microglial activation inhibition. NAC only inhibits microglial activation by an indirect route anyway.

 

[nandixon]

In addition to inhibition of inappropriately activated microglia, another possibility for reducing their impact might be to reduce their numbers, e.g. via CSF1R inhibitors:

Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain
http://www.cell.com/neuron/fulltext/S0896-6273(14)00171-8

The colony-stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microglia in the brain that originates from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within 1 week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin-positive cells that then differentiate into microglia.

(BTW, I found the above reference within the following article, which demonstrates how microglia can easily be involved in how certain foods can exacerbate ME/CFS symptoms:
Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function
http://www.cell.com/cell-reports/abstract/S2211-1247(14)00972-3)

 

[Hip]

In addition to inhibition of inappropriately activated microglia, another possibility for reducing their impact might be to reduce their numbers, e.g. via CSF1R inhibitors:

An interesting idea.

I did a quick search, but unfortunately there do not seem to be any CSF1R inhibitor drugs licensed for use.

 

[OverTheHills]

The NAC is now making me too sleepy, so I am cutting back on that. Still need the LDN otherwise I get vivid, busy and rather scary dreams all night instead of proper sleep
(imagine something which is a cross between the alien from Alien and a crocodile. Menacing you while you are stuck on a high inaccessible ledge. That sort of dream).

@OverTheHills
Glad you are getting benefits. Though bear in mind it's possible the benefits from NAC might be due to something other than microglial activation inhibition. NAC only inhibits microglial activation by an indirect route anyway.

@Hip I have to confess I have little science education and what I have was 35 years ago, when there was a lot of memorising the periodic table and other random facts. I try new supplements very occasionally on a more-or-less random basis. If you have any speculations as to why NAC has some positive effects for me (apart from inhibiting microglial activation) I am all ears!
OTH