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A Neuroinflammatory Model of ME/CFS - Final Part?

Nielk

Senior Member
Messages
6,970
Thank you, Marco. Excellent comprehensive article full of useful information.
Have you ever looked into neurofeedback for calming the excoticity of the brain? It has been somewhat useful for me.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Thank you, Marco. Excellent comprehensive article full of useful information.
Have you ever looked into neurofeedback for calming the excoticity of the brain? It has been somewhat useful for me.


Thanks Nielk.

Funny you should mention neuro(bio)feedback.

I've recently bought a device which aims to balance the autonomic nervous system which I'm trialing over a one month period and will likely write my experiences up for Health Rising.
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Thanks Marco. I shall air my thoughts to the wider world as I expressed them to you last night. I am most intrigued by Baclofen for obvious reasons:

I was perusing your latest article on HR and in relation to Baclofen. Interestingly, perhaps, I was prescribed this primarily as a muscle relaxant and whilst you mentioned the stiff body syndrome; you didn't really go into this aspect of it. Presumably because you were pursuing your hypothesis.

What is however intriguing to me is that whilst it was prescribed for help with relaxing and thus aiding my aching muscles and for the involuntary twitching; I was also experiencing much in the way of labyrinthine disturbance that in turn caused nausea. I noticed you had referred to tinnitus at one point and that also was an issue.

I also take Betahistine Hydrochloride for the ear/nausea/instability and again I had always assumed - was led to assume - that this was the main drug for dealing with my inner-ear virus-inspired disturbances.

I never really looked beyond what is said on the medication leaflets to be honest; but it is intriguing that something taken principally for one thing could be aiding something else - e.g. the theory of neuroinflammation - don't you think? Ironic even.

That said, my doses of Baclofen, whilst I think quite high, may not be significant. However, I shall I think look into the drug further.

Hope to get back to the substance of your article later today. Thanks for highlighting it here :)
 

Nielk

Senior Member
Messages
6,970
Thanks Nielk.

Funny you should mention neuro(bio)feedback.

I've recently bought a device which aims to balance the autonomic nervous system which I'm trialing over a one month period and will likely write my experiences up for Health Rising.


I am looking forward to reading about your experience. I have use the pRoshi system with some benefit.
 

natasa778

Senior Member
Messages
1,774
Thanks Nielk.

Funny you should mention neuro(bio)feedback.

I've recently bought a device which aims to balance the autonomic nervous system which I'm trialing over a one month period and will likely write my experiences up for Health Rising.

Could you post the link or more details on the device please?
 

natasa778

Senior Member
Messages
1,774
Thanks for the article Marco! Wondering if you came across Ibudilast when searching for potential treatments? It is a potent antiinflammatory from Japan, licenced there for few conditions and now in trials for neuropathic pain, opioid withdrawal and chronic migraine. Has some promise for MS ... Migraine trial researchers are expecting glutamate levels to serve as biomarkers

PS the mechanism behind its expected effects in drug withdrawal symptoms is calming of glial activation
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
Baclofen on its own i dont find sedating but when combined with other sleep meds i find it improves the depth and quality of sleep. It has been mentioned in other artilces as the poor mans XYREM which increases deep sleep stage 4 etc. I have also read that tolerance doesnt occur but in my experience it does just like everything else, so i find it good to use intermittently. The highest i have used at once is 75mg, but i find 25mg is enough to help sleep and is the dose i have settled on. I have used it during the day for headaches etc and it has helped but i havent used it alot outside of helping sleep. As for a muscle relaxer i have found its not that good especially with back pain, but thats my experience. Another muscle relaxer tizanadine i have found the same thing, but it does help sleep. For me the best thing i have found for muscle relaxation is lyrica.

Its good to see these drugs investigated deeper then just their muscle relaxing qualities.

cheers!!
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Thanks for the article Marco! Wondering if you came across Ibudilast when searching for potential treatments? It is a potent antiinflammatory from Japan, licenced there for few conditions and now in trials for neuropathic pain, opioid withdrawal and chronic migraine. Has some promise for MS ... Migraine trial researchers are expecting glutamate levels to serve as biomarkers

PS the mechanism behind its expected effects in drug withdrawal symptoms is calming of glial activation


Wow!

Thanks Natasha. That's a new one for me and while I've only skimmed the paper (I'll print it off and read it later) Ibudilast appears to hit all the right targets. Glial cells (astrocytes and microglia) appear to be key to controlling neuroinflammation.

This caught my eye (bolds added) :

In vitro, ibudilast is capable of attenuating kainite-induced oligodendrocyte cell toxicity [14,15] and astrocyte apoptosis induced in an in vitro model of reperfusion [16]. Microglial activation is dose dependently reduced by ibudilast [17,18,19] with reductions in lipopolysaccharide induced nitric oxide, reactive oxygen species,
interleukin-1β, interleukin-6, and TNF-α production and enhanced production of the antiinflammatory
cytokine, interleukin-10 [17].



Based on what I'd outlined in this and previous blogs, I've tried to summarise the model in diagram form :

Gating diagram.jpg



Notes :

A neuroinflammatory cycle may be triggered by a variety of infective, physiological or psychological stressors in individuals with genetic of acquired predispositions.

Pro-inflammatory cytokines (potentially via attenuated clearance of extracellular glutamate by glial cells) trigger a 'vicious cycle' of neuroinflammation which in itself may be self-perpetuating via 'feed- forward' mechanisms / 'kindling'. The neuroinflammatory cycle depletes antioxidant capacity which feeds back as a perpetuating 'stressor'.

Neuroinflammtion may result in neural loss in the pre-frontal cortex compromising inhibitory mechanisms resulting in deficits in executive function, attentional mechanisms, working memory, sensory gating and vagal tone which in turn results in a state of autonomic nervous system 'sympathetic dominance'. Neuroinflammation may also result in peripheral and autonomic neuropathies. Together these mechanisms result in increased pain and nociception, fatigue, exercise intolerance, postural hypotension etc. Again these effects feed back as perpetuating stressors.
Chronic sympathetic dominance is associated with reduced GABA, reduced stress resilience, reduced immune function (which may allow viral persistence) and is essentially a pro-inflammatory state increasing oxidative stress and the production of pro-inflammatory cytokines which in turn further stimulates the neuroinflammatory cycle.

Persistent sympathetic activity may attenuate the production of protective (against ROS and glutamate excitotoxicity) heat shock proteins (HSPs) – a degenerative deficit also found in ageing.

This model is potentially self sustaining at the neuroinflammation level and as a global system.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
I am looking forward to reading about your experience. I have use the pRoshi system with some benefit.


Interesting. I initially thought the last thing our nervous systems need is additional novel stimuli but they so suggest that it can help break repeating stress related thoughts and re-orient attention. Several studies suggest there are attention orientation problems in ME/CFS.
 

vli

Senior Member
Messages
653
Location
CA
Wow!

Thanks Natasha. That's a new one for me and while I've only skimmed the paper (I'll print it off and read it later) Ibudilast appears to hit all the right targets. Glial cells (astrocytes and microglia) appear to be key to controlling neuroinflammation.
Can someone explain to me how glial cell attenuation helps us? I didn't know what glial cells were so I read up on them on wikipedia and I'd think they sounded like something we want more of, not less (which is what I thought attenuation meant?). Thank you!
PS. I ask because I live in Asia where I can ask my doctor if he can get ibudilast.
 

beaverfury

beaverfury
Messages
503
Location
West Australia
Anyone ever tried Ibudilast ? Or any other microglial inhibitors?

Or Ibuprofen? Wiki - microglia
Non-steroidal anti-inflammatory drugs (NSAIDs) have proven to be effective in reducing the risk of AD.[17] "Sustained treatment with NSAIDs lowers the risk of AD by 55%, delays disease onset, attenuates symptomatic severity and slows the loss of cognitive abilities. The main cellular target for NSAIDs is thought to be microglia. This is supported by the fact that in patients taking NSAIDs the number of activated microglia is decreased by 65%."[17]

I'm suspect that ibuprofen caused some of my problems in the first place.
I was taking it excessively and may have wiped out the mucus lining of my gut in the week i became ill.
http://www.ncbi.nlm.nih.gov/pubmed/22776871 Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes.

It also depletes glutathione.

But maybe if used correctly it may help with neuroinflammation. Just speculation.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Anyone ever tried Ibudilast ? Or any other microglial inhibitors?

Or Ibuprofen? Wiki - microglia
Non-steroidal anti-inflammatory drugs (NSAIDs) have proven to be effective in reducing the risk of AD.[17] "Sustained treatment with NSAIDs lowers the risk of AD by 55%, delays disease onset, attenuates symptomatic severity and slows the loss of cognitive abilities. The main cellular target for NSAIDs is thought to be microglia. This is supported by the fact that in patients taking NSAIDs the number of activated microglia is decreased by 65%."[17]

I'm suspect that ibuprofen caused some of my problems in the first place.
I was taking it excessively and may have wiped out the mucus lining of my gut in the week i became ill.
http://www.ncbi.nlm.nih.gov/pubmed/22776871 Aggravation of exercise-induced intestinal injury by Ibuprofenin athletes.

It also depletes glutathione.

But maybe if used correctly it may help with neuroinflammation. Just speculation.

Wow - I didn't know that there actually was evidence that exertion causes gut problems. Thank you for the link - I have saved it. It seems to fit with the leaky-gut model perfectly, including the fact that some or many of us experience an exacerbation of gut problems as part of PEM. I had theorised that it was due to acidosis of the muscles going on to acidify the gut via a reduction of the blood pH, all involving lactic acid. Maybe it is then...

I am excited about this piece of the jigsaw puzzle! :)
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Anyone ever tried Ibudilast ? Or any other microglial inhibitors?

Or Ibuprofen? Wiki - microglia
Non-steroidal anti-inflammatory drugs (NSAIDs) have proven to be effective in reducing the risk of AD.[17] "Sustained treatment with NSAIDs lowers the risk of AD by 55%, delays disease onset, attenuates symptomatic severity and slows the loss of cognitive abilities. The main cellular target for NSAIDs is thought to be microglia. This is supported by the fact that in patients taking NSAIDs the number of activated microglia is decreased by 65%."[17]

I'm suspect that ibuprofen caused some of my problems in the first place.
I was taking it excessively and may have wiped out the mucus lining of my gut in the week i became ill.
http://www.ncbi.nlm.nih.gov/pubmed/22776871 Aggravation of exercise-induced intestinal injury by Ibuprofenin athletes.

It also depletes glutathione.

But maybe if used correctly it may help with neuroinflammation. Just speculation.


As far as I know ibuprofen (nothing kills a headache like neurofen for me but I only take it occasionally) is a non selective cox-2 inhibitor which explains its adverse effects on the stomach. In contrast celebrex is a selective cox-2 inhibitor that might help tackle neuroinflammation while avoiding the stomach issues.