Hip
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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
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
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