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

[Hip]

Chronic microglial activation (a long-term inflammatory state in the brain) has been shown to exist in ME/CFS. 1

When activated, microglia can produce high quantities of the excitatory neurotransmitter glutamate. 1 2 So when microglia are chronically activated, as they are in ME/CFS, this may result in high levels of glutamate in the brain, which can over-activate NMDA receptors and in turn overexcite neurons. High levels of glutamate in the brain have been suggested as a possible cause of the neurological symptoms of ME/CFS (such as brain fog, fatigue and sensory gating deficits).

Chronic microglial activation occurs in persistent coxsackievirus B infections of the central nervous system, 1 and of course coxsackievirus B is strongly linked to ME/CFS. Thus a coxsackievirus B infection of the brain may in part explain why chronic microglial activation is present in ME/CFS.

Diseases that also exhibit chronic microglial activation include: hepatitis C, 1 Lyme neuroborreliosis, 1 systemic lupus erythematosus, 1 schizophrenia 1 and bipolar disorder; 1 interestingly the first three in this list have very similar fatigue and brain fog symptoms to ME/CFS, suggesting that these symptoms may be underpinned by chronic microglial activation.

In order to reduce these ME/CFS symptoms of fatigue and brain fog, inhibiting microglial activation may be a good strategy.

Given below are lists of supplements and drugs that inhibit microglial activation, and inhibit the pro-inflammatory cytokines released from activated microglia.

Note that some of the studies relating to the microglial inhibitors below are in vitro studies, and with these, the microglial inhibition may not work when the supplement or drug is taken orally and used in vivo. With in vitro studies, they use a certain concentration of the drug or supplement in a cell line to achieve microglial inhibition. But that concentration may be too high to achieve in the body when the drug or supplement is taken orally.



Inhibitors of Microglial Activation

All the following may have beneficial effects in lowering microglial activation and brain inflammation:

Valcyte (valganciclovir) and Cytovene (ganciclovir) potently inhibit microglial activation. 1
• EDIT: a new study indicates that in fact ganciclovir and valganciclovir do not inhibit microglial activation.
Low-dose naltrexone (LDN) appears to block the TLR-4 receptor on microglia, inhibiting microglial activation. 1
Nimodipine reduces microglial activation in the locus coeruleus and substantia nigra pars compacta. 1
Hyaluronic acid (a supplement) reduces microglial activation by a TLR-4 receptor mechanism (like LDN) 1
Lithium significantly inhibits LPS-induced microglial activation, via suppression of LPS-induced TLR-4 expression. 1
Ar-turmerone (found within turmeric) 1
Vitamin E 1
Wogonin (flavonoid from skullcap herb) 1
Baicalein (flavonoid from skullcap herb) blocks LPS-induced activation of microglia. 1
Silymarin (found within milk thistle herb) significantly inhibits the LPS-induced activation of microglia. 1
Genistein (a flavonoid supplement) 1
Lycopene 1
Tetracyclines (a class of antibiotic, which includes minocycline, doxycycline and tetracycline) inhibit ischemia-induced activation of microglia. 1
Minocycline (antibiotic) 1
Blueberries 1
Sulforaphane (a supplement, obtained from cruciferous vegetables) 1
Acupuncture 1
N-acetyl-glucosamine 1
Sesame seed oil 1
Andrographolide (from the herb Andrographis paniculata) 1
Acetate (which you can get from vinegar) inhibits microglial activation in a rat model of Lyme disease. 1
Cannabidiol (non psychoactive component of Cannabis, available as Cibdex and Dew Drops Hemp Oil). 1
Dextromethorphan (a cough mixture cough suppressant) 1
Siberian ginseng (Eleutherococcus senticosus) appears to inhibit microglial activation. 1
Ginsenoside Rg3 (from Panax ginseng) 1
Gastrodia elata (a Chinese herb, aka: Tian Ma) 1
Isodojaponin D (from the herb Isodon japonicus) 1
Tetrandrine (from the Chinese herb Stephania tetrandra, aka: Han Fang Ji) 1
Risperidone (antipsychotic drug) significantly inhibits interferon gamma-induced microglial activation in vitro. 1
Terminalia chebula (Indian herb) inhibits LPS-induced microglia activation. 1
Resveratrol may reduce microglial activation. 1
Memantine (NMDA receptor-blocking drug) reduces microglial activation. 1
Palmitoylethanolamide (PEA) reduces microglial activation induced by formalin or MPTP. 1 2
Astrocyte-derived GDNF, which is a neural growth factor, is a potent inhibitor of microglial activation, 1 and the herb Rehmannia glutinosa induces GDNF, 1 as does ibogaine 1 which is found in the psychedelic herb Iboga (the benefits of Iboga can be obtained at low doses, below the threshold of its psychedelic effects); ibogaine may also help Parkinson's, as GDNF helps protect and regenerate dopamine neurons.
Elderberry extract 1


Inhibitors of Inflammatory Cytokine Release from Activated Microglia

All the following may have beneficial effects by reducing the inflammatory cytokines released by activated microglia:

Pycnogenol lowers TNF-α, IL-6 and IL-1β from LPS-stimulated microglia. 1
Phytoestrogens lower inflammatory cytokines IL-1β, IL-6 and TNF-α. 1
Vinpocetine supplement inhibited the production of nitrite oxide and inflammatory cytokines such as IL-1β, IL-6 and TNF-α in BV-2 microglia. 1
Simvastatin (cholesterol-lowering medication) reduces IL-1β and inhibits the activation of microglial cells in traumatic brain injury. 1
Rifampicin (antibiotic) inhibits nitric oxide, iNOS, COX-2, IL-1β, TNF-α and prostaglandin E2 from LPS- stimulated microglia. 1
Propentofylline inhibits LPS-induced release of IL-1β and TNF-α from activated microglia. 1
Ceftriaxone (injectable antibiotic) reduced IL-1β released from microglia during ischemia. 1
Sulforaphane attenuates the LPS-induced increase of IL-1β, IL-6 and TNF-α expression in microglia. 1
Obovatol (from Magnolia officinalis) attenuates microglia-mediated neuroinflammation. 1
Spironolactone inhibits TNF-α release (by 50% to 60% at 10 µM) from LPS-activated microglia. 1
Ibudilast (a Japanese drug which inhibits TLR-4) suppresses the production of nitric oxide, reactive oxygen species, IL-1β, IL-6, TNF-α and enhanced the production of IL-10. 1
Inflexin significantly inhibits the release of nitric oxide from microglia. 1
Piper kadsura (Japanese pepper) inhibits IL-1β and TNF-α release from microglia. 1
Reishi (Ganoderma lucidum) inhibits nitric oxide, IL-1β and TNF-α release from microglia. 1
Magnesium sulfate inhibits the release of iNOS, nitric oxide, prostaglandin E2, IL-1β and TNF-α in LPS-activated microglia. 1
Amantadine reduces the release of pro-inflammatory factors from activated microglia. 1
SSRI antidepressants potently inhibit microglial TNF-α and nitric oxide production in microglia. 1
Curcumin (found within turmeric) blocks the production of nitric oxide, TNF-α, IL-1α and IL-6 in IFN-gamma- and LPS-stimulated microglia. 1
Icariin (from the herb Epimedium, aka: horny goat weed) significantly inhibits nitric oxide, prostaglandin E2, reactive oxygen species, IL-1β, IL-6 and TNF-α in LPS-activated microglia. 1 Note that icariin's oral bioavailability is only 12%, but rises to 40-62% if taken with a lactase inhibitor. 1
Luteolin (flavonoid supplement) inhibits LPS-induced release of nitric oxide, COX-2, TNF-α, IL-1β, IL-6 and prostaglandin E2 from microglia. 1 2
Fisetin (a flavonoid supplement, found in strawberries and mangoes) markedly suppresses nitric oxide, iNOS, TNF-α, IL-1β, COX-2, and prostaglandin E2 in LPS-stimulated microglia cells. 1
Pioglitazone (Actos) inhibits nitric oxide, iNOS, TNF-α, IL-6 and IL-1β production in LPS-stimulated microglia. 1
Oxymatrine inhibits production of nitric oxide, iNOS, PGE2, COX-2, TNF-α, IL-1β and IL-6 in LPS-stimulated BV2 microglial cells. 1 Oxymatrine also down-regulates TLR-2 and TLR-4. 1
Beta-glucans attenuates TLR-2- and TLR-4-mediated cytokine production by microglia. 1
Omeprazole and lansoprazole (proton pump inhibitors) are anti-inflammatory and reduce microglial neurotoxicity. 1



Inhibitors of Inflammatory Cytokine Release from Astrocytes

The activities of astrocyte cells in the brain are closely tied in with the process of microglial activation. All the following may have beneficial effects by reducing the inflammatory cytokines released by astrocytes:

Rehmannia glutinosa steamed root reduces astrocyte IL-1 and TNF-a secretion. 1 This steamed (cooked) Rehmannia glutinosa root has the Chinese name Shu Di Huang. This is slightly different to raw (uncooked) Rehmannia glutinosa root, whose Chinese name is Sheng Di Huang. The latter is prone to causing strong stomach aches.
Dandelion (Taraxacum officinale) decreased TNF-α secretion from rat astrocytes. 1
Alpha lipoic acid decreased IL-1β, TNF-α, IL-6 and iNOS secretion from astrocytes. 1
Resveratrol decreased the expression of TNF-α, IL-6, iNOS and NO in astrocytes. 1 2
Dimethyl fumarate (Tecfidera, a very expensive drug) decreased the expression of IL-1β, TNF-α, IL-6 and NO in astrocytes. 1



Inhibitors of Glutamate Release from Activated Microglia

Carbenoxolone 1



Inducers of Microglial Activation

The following substances increase microglial activation and brain inflammation, and will likely worsen ME/CFS symptoms:

Lipopolysaccharide (LPS), which derives from Gram negative bacteria, increases microglial activation.
Interferon gamma, which is secreted by the body during infection, increases microglial activation.
Homocysteine promotes proliferation and activation of microglia. 1


To counter this increase microglial activation by the above factors, note that:

• Andrographolide (from the herb Andrographis paniculata) inhibits interferon gamma. 1

• Increasing methylation (such as by the methylation protocol) reduces homocysteine, which will then reduce microglial activation. Indeed, the fact that methylation reduces homocysteine levels may help explain why the methylation protocol appears to be beneficial for ME/CFS. The most important supplements for reducing homocysteine are: folate, the vitamins B12, B6 and B2, zinc and trimethylglycine. 1 Other homocysteine-reducing supplements include: N-acetyl-cysteine reduces plasma homocysteine levels. 1 Phytic acid (aka: inositol hexaphosphate or IP6) is a supplement that reduces plasma homocysteine. 1 Choline or betaine reduces homocysteine. 1



Inducers of Inflammatory Cytokine Release from Microglia

The following substances increase the release of pro-inflammatory cytokines from activated microglia, and will likely worsen ME/CFS symptoms:

Leptin (a hormone) induces IL-1β release from rat microglia. 1 Leptin may also increase IL-6 release from microglia. 1
Lactate induces IL-1β, IL-6 and TNF-α release from rat microglia, as well as IL-6 and TNF-α release from rat astrocytes. 1 Lactate is produced by the muscles during exercise, and can cross the blood-brain barrier quite easily.



The Two Main Types of Microglial Activation

There are actually two main modes of microglial activation:

Classical microglial activation (M1 mode) which is neurodestructive (and involves COX-2, iNOS, IL-6, and TNF-alpha).

Alternative microglial activation (M2 mode) which is neuroprotective (and involves FIZZ-1, YM-1, Arginase-1, and IL-4).

Classical microglial activation is the "kill" mode which destroys pathogens in the brain; alternative microglial activation is the repair mode which heals the brain. When we talk about "microglial activation" and is destructive effects, we are tacitly referring to classical microglial activation.

(There is also a recently discovered third mode of microglial activation called acquired deactivation, which is similar to alternative activation in that it is also an anti-inflammatory and repair mode of microglia).

Classically activated microglia are also known as M1 phenotype microglia. Alternatively activated microglia and microglia under acquired deactivation are also known as M2 phenotype microglia.



Factors that Switch off the Microglial M2 Neuroprotective Mode, and Switch on the M1 Neurodestructive Mode

Oxidative stress and lack of Nrf2 may favor the neurodestructive (classical) M1 mode of microglial activation over the neuroprotective (alternative) M2 mode. 1 Thus taking Nrf2-activators may help flip to the neuroprotective microglial activation mode. Sulforaphane is the most potent natural activator of Nrf2. 1 Genistein, sulforaphane, EGCG, resveratrol, pterostilbene, zeaxanthin, lutein, agmatine and artesunate activate Nrf2. There are Nrf2-activator supplements like this one: XYMOGEN Nrf2-activator. Curcumin also activates Nrf2. 1 Ozone therapy activates Nrf2. 1 Hyperbaric oxygen therapy (HBOT) activates Nrf2. 1 Caryophyllene activates Nrf2. 1 Artesunate activates Nrf2. 1 A list of Nrf2 activators given here.

NADPH oxidase promotes the neurodestructive (classical) phenotype of microglial activation over the neuroprotective (alternative) phenotype. NADPH oxidase is a membrane-bound enzyme found on microglia and macrophages; this enzyme generates the free radical superoxide in order to kill pathogens. Apocynin (also called acetovanillone) from the herb Picrorhiza kurroa is a potent NADPH oxidase inhibitor, and promotes the neuroprotective microglial mode. 1 Apocynin inhibits NADPH oxidase by preventing the assembly of this enzyme. Phycocyanobilin, which makes up about 1% of spirulina, is also a potent NADPH oxidase inhibitor. 1

Lipopolysaccharide (LPS) from gram negative bacteria seems to switch microglia from their M2 neuroprotective mode into their M1 neurodestructive mode. Thus if any LPS was getting into the brain (perhaps from a leaky gut, from a gram negative sinus infection, or even a gram negative bacterial infection within the brain), then this would tend to promote the M1 neurodestructive mode of microglia, and prevent the activation of the M2 neuroprotective mode of microglia. Though note that very little LPS passes through an intact blood-brain barrier. 1

On the other hand, repeated exposure to LPS seems to cause endotoxin tolerance and shifts microglial polarization toward a M2-like phenotype. In addition, repeated exposure to LPS causes repression of pro-inflammatory factors and increased expression of factors that mediate the resolution of inflammation. 1

Interferon gamma promotes the M1 neurodestructive mode of microglia. 1

Ochratoxin A, a mycotoxin which Dr Joseph Brewer found in 83% of ME/CFS patients, and in zero percent of healthy controls, 1 promotes the neurodestructive mode of microglial activation. 1



Switching on the M2 Neuroprotective Mode of Microglia

Rutin promotes the M2 neuroprotective mode. 1 The Th2 cytokine IL-4 promotes M2 microglia, as does the cytokine IL-13. 1 Minocycline inhibits M1 microglia. 1

Atorvastatin inhibits M1 and enhances M2 in mice with brain injury. 1



Notes

Hyaluronic acid appears to inhibit microglia activation by acting on the TLR-4 receptor, just as LDN does. So hyaluronic acid, which is available as a supplement, may be a good alternative (or an adjunct) to LDN. Some other TLR-4 antagonists are given here. Oxymatrine also has TLR-4 and TLR-2 effects: it down-regulates the the expression of these two receptors in the brain.




Further Reading

Inhibitors of Microglial Neurotoxicity: Focus on Natural Products
Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders

 

[SDSue]

This is fabulous, @Hip - very well organized, easy to read, and useful. Thanks.

 

[Ema]

Interesting that the article mentions blueberries...and there is a liquid blueberry hyaluronic acid product on Amazon.

Wonder what the effective HA dose is? Did I miss it?

Great work!

 

[Gingergrrl]

@Hip Thank you so much for putting all of that information together!!! I am going to need to print it out and read through it multiple times to try to grasp it all.

But I can definitely start eating blueberries... It's interesting b/c one of my best friends has epilepsy and her neurologist has told her multiple times that blueberries are one of the most helpful foods that she should be eating and we never really knew why!

ETA- What is hyaluronic acid?

 

[Marco]

Very comprehensive Hip. Thanks.

Just to note that in the scenario of CNS coxsackievirus B infection (or any other infection of the brain) the 'classical' activation is the brain resident macrophages trying to do their job of eliminating the infection so I'm not sure that inhibition would necessarily be a good thing. At least as far as an acute infection is concerned.

 

[RustyJ]

Very comprehensive Hip. Thanks.

Just to note that in the scenario of CNS coxsackievirus B infection (or any other infection of the brain) the 'classical' activation is the brain resident macrophages trying to do their job of eliminating the infection so I'm not sure that inhibition would necessarily be a good thing. At least as far as an acute infection is concerned.

Does anyone have more info on the possible negatives of inhibition of microglial activity. And limiting TFNa in particular?

 

[Marco]

Does anyone have more info on the possible negatives of inhibition of microglial activity. And limiting TFNa in particular?

This might be worth a read :

Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558702/

 

[lansbergen]

Just to note that in the scenario of CNS coxsackievirus B infection (or any other infection of the brain) the 'classical' activation is the brain resident macrophages trying to do their job of eliminating the infection so I'm not sure that inhibition would necessarily be a good thing. At least as far as an acute infection is concerned.

And activated chronic infections.

 

[Hip]

in the scenario of CNS coxsackievirus B infection (or any other infection of the brain) the 'classical' activation is the brain resident macrophages trying to do their job of eliminating the infection so I'm not sure that inhibition would necessarily be a good thing.

That's true.

Although, one might also consider the opposite hypothesis: that chronic microglial activation might be preventing viral clearance from the brain. One of the cytokines released by activated microglia is IL-6, and this paper explains that IL-6 promotes Th2 and simultaneously inhibits Th1 through two different mechanisms.

So the IL-6 released by activated microglia might actually be inhibiting the Th1 immune response in the brain, and thus inhibiting antiviral immunity in the brain. (Although I am not sure if that paper applies to the brain, as it involves T cells).

Out of the drugs and supplements listed above, the ones that reduce IL-6 release from activated microglia are:

Inhibitors of IL-6 secretion from activated microglia:
Phytoestrogens
Vinpocetine
Sulforaphane
Ibudilast
Horny goat weed (Epimedium)
Luteolin
Pioglitazone (Actos)
Oxymatrine

(As an aside: I tend to think that IL-6 may also be responsible for the exercise-derived PEM symptoms in ME/CFS: many patients report a worsening of viral symptoms after exercise, and exercise generates massive amounts of IL-6 in the body — up to a 100-fold increase in plasma levels of IL-6 can occur after exercise. 1)



There is evidence to suggest that microglial activation inhibition is beneficial in ME/CFS:

Valcyte is a potent inhibitor of microglial activation, as well as an antiviral and immunomodulator, and many ME/CFS patients do well on Valcyte. LDN also inhibits microglial activation, and again lots ME/CFS patients benefit from this.

Homocysteine promotes microglial activation, and the methylation protocol supplements folate and vitamin B12 reduce homocysteine, thus countering microglial activation. Again, quite a few ME/CFS patients do well on the methylation protocol.




Note also that there are several different possible strategies contained within the above list of drugs and supplements which inhibit microglia:

• One could try some of the drugs and supplements that simply lower microglial activation.

• One could try countering some of the factors that increase microglial activation. Lipopolysaccharide, interferon gamma and homocysteine all increase microglial activation.

• One could try some of the drugs and supplements that lower the release of inflammatory cytokines from microglia.

• One could try some of the drugs and supplements that lower the release of inflammatory cytokines from astrocytes. In studies, coxsackievirus B, a virus strongly linked to ME/CFS, has been found to infect astrocytes, and then cause the chronic release of inflammatory cytokines from these infected astrocytes. 1 2 An autopsy on an ME/CFS patient also found coxsackievirus B in the glial cells / astrocytes. 1 So perhaps inhibiting the release of inflammatory cytokines from astrocytes might be beneficial.

• One could try some of the drugs and supplements that help switch activated microglia from their neurodestructive mode (the "kill mode") to the neuroprotective mode (the "heal and repair" mode). Activated microglia do not have to operate in this neurodestructive mode, they can also operate in the neuroprotective mode. Drugs and supplements that help switch activated microglia to the neuroprotective mode include: genistein, sulforaphane and artesunate.

 

[SDSue]

Horny goat weed

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

 

[heapsreal]

Valcyte is a potent inhibitor of microglial activation, as well as an antiviral and immunomodulator, and many ME/CFS patients do well on Valcyte.

Have you seen any information on how long this takes to occur?

My thoughts are that most things that reduce inflammation should have effects atleast within a couple of weeks if not alot sooner, thats if its actions are only working on microglial activation, but i really dont know??

Many dont feel better from valcyte until they have been on it for months and many feel really bad when first starting this?

Another thing i have noticed is that those who are positive responders who have relapsed down the track, do seem to respond much quicker and dont seem to go through as bad of a time when restarting valcyte and improve much quicker the second time around. One possible reason for this is that the first time the viral load may have been alot higher and the relapse was caught alot earlier the second time so viral load wasnt as high?

It would be interesting to see valcyte used in those with no active viral infections and see the response.

 

[heapsreal]

Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation.

Memantine shows clinically relevant efficacy in patients with Alzheimer's disease and Parkinson's disease. Most in vivo and in vitro studies attribute the neuroprotective effects of memantine to the blockade of N-methyl-D-aspartate (NMDA) receptor on neurons. However, it cannot be excluded that mechanisms other than NMDA receptor blockade may contribute to the neuroprotective effects of this compound. To address this question, primary midbrain neuron-glia cultures and reconstituted cultures were used, and lipopolysaccharide (LPS), an endotoxin from bacteria, was used to produce inflammation-mediated dopaminergic (DA) neuronal death. Here, we show that memantine exerted both potent neurotrophic and neuroprotective effects on DA neurons in rat neuron-glia cultures. The neurotrophic effect of memantine was glia dependent, as memantine failed to show any positive effect on DA neurons in neuron-enriched cultures. More specifically, it seems to be that astroglia, not microglia, are the source of the memantine-elicited neurotrophic effects through the increased production of glial cell line-derived neurotrophic factor (GDNF). Mechanistic studies showed that GDNF upregulation was associated with histone hyperacetylation by inhibiting the cellular histone deacetylase activity. In addition, memantine also displays neuroprotective effects against LPS-induced DA neuronal damage through its inhibition of microglia activation showed by both OX-42 immunostaining and reduction of pro-inflammatory factor production, such as extracellular superoxide anion, intracellular reactive oxygen species, nitric oxide, prostaglandin E(2), and tumor necrosis factor-alpha. These results suggest that the neuroprotective effects of memantine shown in our cell culture studies are mediated in part through alternative novel mechanisms by reducing microglia-associated inflammation and by stimulating neurotrophic factor release from astroglia.

http://www.ncbi.nlm.nih.gov/pubmed/19536110

Plenty more research with memantine and neuroinflammation.

 

[lansbergen]

One possible reason for this is that the first time the viral load may have been alot higher and the relapse was caught alot earlier the second time so viral load wasnt as high?

Yes

 

[Hip]

Have you seen any information on how long this takes to occur?

My thoughts are that most things that reduce inflammation should have effects atleast within a couple of weeks if not alot sooner, thats if its actions are only working on microglial activation,

It says here that microglia can activate with 30 minutes (in ischemia).



Microglial Priming

However, once microglia have been activated, they can then become more "trigger happy" and mount exaggerated responses to subsequent activation events. This is known as "priming",

Priming is where the first exposure to an inflammatory factor (such as IFN-γ or LPS) conditions immune cells like microglia to become more sensitive to reacting to any further exposures, so that subsequent exposures to inflammatory factors then create much stronger inflammatory responses from these immune cells.

For example, it has been found that:

in macrophages that have previously been exposed to IFN-γ (the priming stimulus), exposure to a triggering stimulus, such as LPS, leads to an exaggerated production of pro-inflammatory cytokines. Priming of macrophages involves several molecular mechanisms, including upregulation of Toll-like receptors (TLRs).

Source: here.

Priming involves both increased sensitization to inflammatory stimuli ("trigger happy"), and a stronger response:

In the case of priming, microglia are not just exhibiting and enhanced toxic microglial response. Rather, in the case of priming, the microglial phenotype shifts, where a much lower stimulus is needed to exact a toxic microglial response.

Source: here.

Microglia activating in order to control a low level viral brain infection with say coxsackievirus B is one thing; but microglia becoming "trigger happy" and mounting much stronger than normal responses is quite another. You would want microglia to activate in a proportionate manner to keep viral infections under control; but you probably don't want over-exaggerated microglial responses that produce too much inflammation and damage in the brain.

There is a Phoenix Rising article about priming as a possible factor in ME/CFS, which says:

Perry and Younger pointed to the potential of microglial inhibitor drugs to calm down the overactive cells or prevent activation in the first place. No microglial inhibitors have been proven to treat ME/CFS or fibromyalgia, but Younger has already run an intriguing small study of low-dose naltrexone (LDN) for fibromyalgia with encouraging results.

Source: Part 2: Brain Cells Making us Sick? Messed up microglia could be driving symptoms

Toll-Like Receptors Involved in Microglial Priming

It's interesting that upregulation of Toll-like receptors is involved in priming. This suggests that medications which antagonize TLR activation would reduce the over-exaggerated microglial responses, yet allow the normal proportionate microglial immune response to fight brain infections.

If you look at the list of microglial inhibitors at the beginning of this thread, you will see it is low-dose naltrexone, hyaluronic acid and lithium that antagonize TLR4. So these might be useful to counter microglial priming, and the over-exaggerated inflammatory response priming can cause.

Though other TLRs also play a role in priming: this paper says that TLR2, TLR3 and TLR4 are involved in microglial priming. The paper says that:

Each TLR recognizes a specific array of pathogen-associated molecular patterns (PAMPs):

TLR3 specifically engages double-stranded RNA, indicating a role in host defence against viruses.
TLR2 shows affinity for a wide range of PAMPs originating from bacteria, virues, fungi and parasites.
TLR4 is triggered not only by lipopolysaccharides (LPS) from Gram-negative bacteria, but also recognizes danger-associated molecular patterns released by injured tissue.

It's interesting that TLR3 is the cell's detector of viral dsRNA, and TLR3 is thus triggered by dsRNA. Given that noncytolytic enterovirus infections, which are thought (by Dr Chia and Profs Chapman and Tracy) to live in the cells of ME/CFS patients, comprise both ssRNA and dsRNA, might these noncytolytic enterovirus infections be constantly triggering TLR3, and thus priming the microglia?

 

[heapsreal]

@Hip sorry the above question was referring to how long valcyte takes to reduce microglial activation?

 

[Hip]

@Hip sorry the above question was referring to how long valcyte takes to reduce microglial activation?

Its says in the full paper on ganciclovir:

Ganciclovir inhibits microglia proliferation

The amelioration of experimental autoimmune encephalomyelitis after ganciclovir treatment was paralleled by strikingly lower numbers of proliferating cells in the brain but not in spleen at 21 d.p.i. (days post infection).

Note that Valcyte is the prodrug for ganciclovir.

They started the ganciclovir treatment in the mice at 7 d.p.i., so that means within two weeks, ganciclovir "strikingly" lowered the numbers of proliferating microglia in the brains of these mice.

 

[Hip]

@heapsreal
I added memantine to the list of microglial activation inhibitors. Thanks.

 

[Hip]

Wonder what the effective HA dose is?

I am not sure, but hyaluronic acid supplements are sold in capsules of around 50 mg to 200 mg. Though how effective these will be, I don't know, because hyaluronic acid is destroyed by stomach acid, but apparently the supplement manufacturers say that they have now devised a way to ensure their product is not destroyed in the stomach.

In my own experiments, I bought some hyaluronic acid powder from purebulk.com, and have applied 400 mg of this transdermally on my body skin, where I hope it will get absorbed.

 

[adreno]

NAG is a precursor to hyaluronic acid.

 

[Sidereal]

I've used transdermal hyaluronic acid. No effect except maybe some increased pain.