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

[Nelly Lenz]

If these are in vivo animal studies, one thing to watch out for is the conversion between animal and human doses. It is not just a case of multiplying the per Kg does by the human body weight to get the human dose. You also have to divide the dosage by a certain factor, a factor of around 12 for mice. See page 7 of this document.

That makes a lot more sense, shows what I know.

 

[Hip]

That makes a lot more sense, shows what I know.

I only learnt about this animal to human dose conversion myself recently, thanks to @nandixon. See this post.

I read that lots of science journalists do not know about this proper method of dose conversion, and just erroneously assume, like I did until recently, that the human dose is obtained by multiplying the mg/Kg animal dose by the human body weight.

 

[AlmostEasy]

I want to throw out there that I have massive success with Adderall. I'm basically convinced at this point that dopamine is a huge issue with me alongside neuro inflammation / chronic immune activation. Adderall itself (D2 agonism) has anti inflammatory properties and boy are they ever strong.

Adderall (though it CAN be hit or miss depending on how often I take it and how my biochemistry is when I do take it) is more powerful to me than my entire methylation protocol hands down. The level of cognition it restores I wouldn't have believed possible if I didn't experience it myself.

With all the supplements I've tried over the past few years the anti inflammatory supplements/drugs and the dopamine agonists have been the strongest. Methylation helps me probably 25% - 30%. Adderall bumps me up to 65% functioning probably when the planets align. It gives me an enlightening glimpse into the reality I used to live in and gives me hope that I can return to normal some day and that what I exist in daily isn't permanent damage, as it reversed before my very eyes.

I haven't looked into the magnitude of it's anti inflammatory properties and I don't enjoy the fact that I use it at all I'd much rather not but it's a real life saver in tight situations where I NEED to focus that day. I also do my best ME/CFS research while on it, it's helped me move forward quite a lot in these regards.

I'll point out too that Ritalin (acute dopamin reuptake inhibitor) helps, but never to the degree of adderall. The direct agonism combined with the dopamine is the sweet spot for my personal biochemistry.

L-Tyrosine and NALT were basically useless. Citicoline is stimulating in a negative way. Choline sources help maybe 3-4%. If it's cheap I'll buy it but I don't sweat it.

I tried minocycline maybe 3 days in a row when I had no idea what I was doing and I attributed a negative response I had with it to it instead of the Vyvanse I was taking. Before methylation I would get crippling depression from amphetamines, now I can tolerate them daily if need be. The people over at the Schizophrenia boards have success with it as well. I did get a positive response but nothing as substantial as Adderall.

• N-A-G was great at first, really great. Seems to have died down. Will test more.
• Memantine is on par with Adderall. It has microglia inhibition, neurotropic factor release, and mild d2 agonism with NMDA antagonism. Money. It gives mild - moderate nausea and at the therapeutic levels can be disorientating.
• LDN I am still playing with. Up to 2.5mg. Comes / goes in waves. I'm not sure which mechanism of it is helping.
• Turmeric used to help a lot; don't feel it anymore.
• Lithium used to help a lot; more than turmeric. Doesn't bring about effects anymore.

It would be interesting to find a similar mechanism of anti inflammation to compare to; I've yet to find it.

Food for thought.

 

[Hip]

Adderall itself (D2 agonism) has anti inflammatory properties and boy are they ever strong.

I came across this study a few years ago which has always intrigued me: it found that agonism of dopamine D2 receptors on astrocytes (not neurons) suppresses neuroinflammation.

This may be of particular significance in ME/CFS, since several brain autopsies have found enterovirus / coxsackievirus B infection in the brains of ME/CFS patients, and in the brain, coxsackievirus B has been shown to infect astrocytes. Thus one might speculate that a lot of the brain inflammation found in ME/CFS might originate in the astrocytes.


This study found that approximately one-third of the total D2 receptor binding sites in the cortex are found on astrocytes. So any dopamine D2 receptor agonists are going to have quite a significant effect on astrocytes in the cortical areas of the brain.

There is a list of various dopamine D2 receptor agonists in this post. The D2 agonist I use is very low dose amisulpride, which works by an auto-receptor mechanism, so that you don't get tolerance build-up problems. I find very low dose amisulpride generally pretty helpful for ME/CFS.

 

[AlmostEasy]

Excellent post, I was hoping you'd have some more insight into this, pleased as always.

There is a list of various dopamine D2 receptor agonists in this post. The D2 agonist I use is very low dose amisulpride, which works by an auto-receptor mechanism, so that you don't get tolerance build-up problems. I find very low dose amisulpride generally pretty helpful for ME/CFS.

That reminds me I did try low dose olanzapine (Zyprexa) for that very reason, without positive effect. This was before methylation. Have you compared the two? I've not tried amisulpride. I've thought a lot about Deprenyl and have tried Uridine Monophosphate. UMP was sketchy, it definitely sped me up quite a bit but I felt like it had lingering sexual dysfunction. I just now remembered about that. Bromantane was amazing if not for its side effect of almost narcolepsy level sleep attacks from the serotonin increase. I get a similar response from 5htp. The dopamine effects though are fantastic. I have odd responses to things.

A few of us are looking into BH4 from China and SAMe as well, that's something I haven't played with and might help significantly with my D2 issue. It at least warrants a trial run, can't say how much it will result in a similar effect.

EDIT - Might be of value to note that I'm + for EBV previous infection (according to classical medical thinking) but according to the ME/CFS Dr's (can't recall which one atm; Lerner?) my levels warrant treatment with an antiviral as it may be a chronic issue. I'm negative for CMV. Haven't been able to test others yet.

 

[Nelly Lenz]

I've been looking for drugs that specifically inhibit astrocyte induced pro inflammatory cytokines/inos release as kind of an adjunct to maybe taking a neuroglia inhbition approach and hoping that helps over time. Its hard to imagine those two aren't directly involved in the fatigue. I figured since response to LDN isn't as great for fatigue as I thought, the problem might lay more in the astrocytes. Here are a couple that weren't on your list.

Statins: Lovastatin, people haven't seem to had great response to, so may not affect the right upregulation pathways or be strong enough/side effects.

Gemfibrozal, hypothesized to be good for cytokine storms and inhibits astrocytes.

Bushi: A toxic Japanese herb, narrow therapeutic range and deadly. Interestingly, the authors noted that attenuating microglia in spinal nerve pain immediately following the injury was effective, attenuating the astrocytes was more effective after a longer duration.

Both Honokiol and Obovatol from Magnolia Officialis.

Andgraphis

Here's an interesting one, Triptolide, from the Thunder God Vine, inhibited astrogliosis and inflammation and promoted spinal cord repair. Triptolide was shown to prevent astrocytes from reactive activation by blocking the JAK2/STAT3 pathway in vitro and in vivo. I get the sense that some the problem is right at the top of spinal column into the brainstem area. Some of the drugs are more effective in different areas of the brain, so it might target the right area. Plus blocking reactive activation sounds right up my alley.

I'm sure the problem is more complex than simply overreactive cytokines production, probably involves some gene dis regulation leading to the neurons in the brainstem not getting enough sugar and oxygen and failing to autoregulate metabolism. Unfortunately I don't have a degree in neurogenetics.

 

[meandthecat]

Made me laugh. Apparently I have the maturity of a 12 year old school boy.

It's a great name and may really work. I started using it when I was recovering from surgery for prostate cancer for obvious reasons!! It was better tolerated than cialis and helped gently. Recovery from surgery confused the ME picture but as the tissues repaired the ME symptoms also eased especially cognitive stuff.

I grow it myself using a European garden form and take it as a tea in the morning as it has a stimulant effect. The autumn leaf is the strongest but I don't measure anything just judge by the colour. If I forget for a while I feel a difference which seems to improve within a day or so of restarting.

 

[meandthecat]

The quote didn't pick up that it was referring to horny goat weed or epimedium which has numerous species on several continent's but was most used in Chinese medicine.

 

[sregan]

Though I am not immune to certain specific supplements causing me ill effects. I cannot take the mineral boron for example. A daily dose of just 3 mg of boron will soon produce very strange emotional effects, making me become extremely sad for no reason, making me feel extremely lonely, even when I am with people. It's horrible. So I avoid boron like the plague. Molybdenum can also do strange things to me in higher doses.

I suspect I am sensitive to Boron also. I've been taking minerals mostly and Boron before bed to process the vitamin D I also take since they are supposed to be synergistic. The Boron capsule is 3mg and I don't hardly ever take an entire one but break it open. But have been taking it regularly for a couple of weeks.

Reading today and Boron can cause a deficiency of B2 and Manganese. I noticed 2 days in a row when I took some coenzymated B1 and B2 in the morning I immediately felt really good which lasted a few hours. My multi-mineral already contains Manganese so I'm going to start supplementing Bs in the AM.

I used to be of the mindset to take only one new thing at a time because when you make changes because if you take more than one thing you won't every know what helped or hurt you. Now I'm finding that taking just one thing can easily cause a deficiency in other things. Taking MB12 for me causes me to need more Potassium (with or without taking Mfolate).

So for me currently the best strategy is to investigate every supplement I take and try to support with co-factors and possibly adjust for genetics based on body feedback and at times intuition helps (maybe AHMO's testing can help?)

 

[Living Dead]

Preventing activation is one thing, but do any of these turn off microglia that have been activated?

 

[carmadw]

You should add, that Cortison or Prednisolon is a potential microglial inhibitor.
http://www.ncbi.nlm.nih.gov/pubmed/10922518
I took it and I felt nearly healthy, only Problem was, that iO had a bad bad benzo withdawal, immediately after the positive results of the Cortison. And, yes I am an fucking Idiot, I took the Cortison for to long, I felt good, but then I had a massive worsening of my condition because of the Cortison, which destroyed my life. I had the Chance of my life to get healthy again amd threw it away. I don't know what happened, dos anyone have any suggestions?

Is there any correlation between Cortison and gaba receptors? Because it felt and it feels like since the worsening of my condition my gaba System donT work anymore. It took a long time, but it felt like I nearly recoverd from my benzo withdawal, but since the unknown NB worsening through the Cortison all the benefits dissapeard.
I am such a fucking Idiot. There is no day, that I dont want to die and no day, that I Am not thinking why I took the Cortison for so long...I know I was left alone by my family and I had deathfear that my old symptomps may c ome back
I am such an Idiot, can't Express how stupid I am
My life is over. I am thinking about suiide a lot.

 

[Thinktank]

How long have you been on hydrocortison and what did your taper schedule look like?
Longterm use of corticosteroids needs to be tapered very slowly, just like benzodiazepines. It may take many months.
If you do it too quickly you may end up with a prolonged suppression of adrenal output. I know of a lupus patient who had to taper 7.5mg prednisolone over a year, any quicker would induce addisons-like symptoms.

Have you had a hormonal checkup? Especially 24h salivary cortisol.

 

[carmadw]

I think about 2 _ 3 months...25 mg
I tappered of quicker then a year, I think2 months.

Didtn have a hormonal Checkup yet, but good advise, thank you

 

[carmadw]

Any further suggestions?

 

[Thinktank]

If you believe it's related to hydrocortison then it's best to have your hormones tested before anything else.

 

[carmadw]

All hormoes? Or some specific?

 

[Biarritz13]

I don't know if this paper was reported but just in case

Artesunate Attenuates Lipopolysaccharide-Stimulated Proinflammatory Responses by Suppressing TLR4, MyD88 Expression, and NF-κB Activation in Microglial Cells.

 

[eljefe19]

@Hip hey hip. I was reading Cort Johnson's latest article at healthrising.org, I think you would find parts of it very interesting. He had some notes from the IAMECFS conference, notably about increased IL-1a in PWME, and how IL-1a is responsible for triggering TNF-a. I referenced your post here, and noticed that while many agents prevent the release of TNF-a, it looks like only Curcumin blocks IL-1a. I have tried to find other agents that do this, but I haven't been able to. Take a look at the piece and let me know what you think!

 

[Biarritz13]

The antiviral drug ganciclovir does not inhibit microglial proliferation and activation.

 

[Hip]

The antiviral drug ganciclovir does not inhibit microglial proliferation and activation.

Very interesting. That study contradicts the earlier study which found ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation.