A Neuroinflammatory Model of ME/CFS - Final Part?

[leokitten]

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

Minocycline and doxycycline have also shown to have exert similar effects on glial cell activation and neuroinflammation and unlike Ibudilast they can be easily prescribed. From my understanding until Ibudilast gets FDA approved for an indication here in the US it's nonexistent.

 

[leokitten]

Just up on Health Rising is the last in my planned series of articles proposing a neuroinflammatory model of ME/CFS.

This part examines research opportunities/potential treatments that logically follow from this theoretical model :

http://www.cortjohnson.org/blog/201...mmation-chronic-fatigue-syndrome-fibromyalgi/

Please feel free to comment

Marco the theory you propose does make sense and I do believe that hyperarousal and sympathetic dominance caused by some underlying factor(s) is key to at least perpetuating this disease (if not causing it) but based on my personal treatment experience I wonder if glutamate is the true source of the problem.

I know I'm only one data point in the sea of CFS sufferers and last year for a while I thought glutamate excitotoxicity was the culprit and I tried Memantine for a very long time and it did absolutely nothing to improve symptoms or alter disease course, I continued to get worse with worse symptoms. I then tried Amantadine for a long time and it had zero positive effect. During this entire time I have been taking all the other supplements you mentioned, CDP-choline, LDN, NAC, and so many more it's too long to list, you name the supplement I have been taking it every day for more than 8 months and they have had zero positive effect. Things only got worse or at minimum stabilized and didn't get better.

 

[Marco]

Marco the theory you propose does make sense and I do believe that hyperarousal and sympathetic dominance caused by some underlying factor(s) is key to at least perpetuating this disease (if not causing it) but based on my personal treatment experience I wonder if glutamate is the true source of the problem.

I know I'm only one data point in the sea of CFS sufferers and last year for a while I thought glutamate excitotoxicity was the culprit and I tried Memantine for a very long time and it did absolutely nothing to improve symptoms or alter disease course, I continued to get worse with worse symptoms. I then tried Amantadine for a long time and it had zero positive effect. During this entire time I have been taking all the other supplements you mentioned, CDP-choline, LDN, NAC, and so many more it's too long to list, you name the supplement I have been taking it every day for more than 8 months and they have had zero positive effect. Things only got worse or at minimum stabilized and didn't get better.

Hi there.

I still feel that neuroinflammation plays a central role in ME/CFS and that glutamate/GABA imbalance results but while the recent PET scan study appears to confirm neuroinflammation in ME/CFS we just don't know enough about the mechanisms as yet to know where or with what to intervene. Hence I was careful not to recommend any particular approach but highlighted areas with research potential.

Re glutamate it may not be elevated levels per se but impaired transport that results in excitotoxic extracellular glutamate and reduced glutamate signalling which could explain cognitive/memory problems. Again - we just don't know and blocking glutamate receptors might just make the problem worse.

There are often 'paradoxical' effects as well - there's too much interaction and negative and positive feedback loops to be able to accurately predict what is likely to happen. Benzodiazepines are now suspected of causing cognitive decline due to 'neurological kindling' following a glutamate rebound spike while long term opioid use is known to exacerbate neuropathic pain. Blocking pro-inflammatory cytokines 'should' help with MS but I believe that in one study TNF-a blockade (I think) actually sped up demyelination.

Even in relatively well characterised conditions such as neuropathic pain where neuroinflammation/microglial activation is pretty well accepted and glial inhibition has great therapeutic potential they still haven't cracked it.

As I'm sure you know microglial activation is a two edged sword - in some circumstances its destructive and in some protective. We really need more research into this area before even thinking of therapeutic approaches - no change is disappointing but symptoms getting worse isn't good at all.

Frustrating as it is I'd wait for the research.

 

[leokitten]

Marco thank you for the nice response, to be clear NMDA antagonists Memantine (and to a lesser extent Amantadine) didn't seem to make anything worse they didn't do anything at all. I fell ill with ME/CFS not long ago in January 2013 and it was a steady decline in health last year and all that comes with the initial downward spiral of this disease.

During this time I was aggressively researching and trying anything and everything that made sense to change the disease course and improve symptoms. In the immense arsenal of things I've tried and done, diet changes, pharmaceutical drugs, supplements, the only things that have made some positive difference are the antivirals I'm taking, Valcyte and Famvir. Everything else has just done absolutely nothing it seems... it feels like they just aren't getting to the true root of the problem. Even Valcyte and Famvir I can feel are only attacking a part of my symptoms so I'm still trying new things all the time in order to find what is perpetuating this disease and preventing full recovery.

 

[leokitten]

In addition to the antiviral and possible immunomodulating properties of Valcyte, relevant to this thread one reason it may also work in ME/CFS is because it's been shown to be a potent microglial inhibitor, here's recent paper from a group at Stanford:

Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation
http://www.ncbi.nlm.nih.gov/pubmed/24493798
http://jem.rupress.org/content/211/2/189.long

 

[kangaSue]

Minocycline and doxycycline have also shown to have exert similar effects on glial cell activation and neuroinflammation and unlike Ibudilast they can be easily prescribed. From my understanding until Ibudilast gets FDA approved for an indication here in the US it's nonexistent.

Just touching on the subject of re-purposing of drugs, cilostazol (Pletal) is very similar in action to ibudilast (both phosphodiesterase inhibitors) with the advantage that it already has FDA approval for use as a treatment for intermittent claudication and warrants further evaluation for off label use in accord with the context of Marco's article.
http://www.onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2009.00615.x/full

It reduced cerebral hypoperfusion in a rodent model and has been used (albeit in limited application) to treat bowel ischemia (Mesenteric ischemia) in humans, a condition where there are episodes of insufficient blood flow to the bowel causing pain and a large lactic acidosis load. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284045/

Similar to the drug that I take for bowel ischemia (Nicorandil), it appears to work in this regard by activating the potassium pathway while selectively blocking calcium influx. http://jpet.aspetjournals.org/content/317/3/1238.abstract

 

[Hide]

Yesterday I was prescribed Ibudilast by the leader of research team in Japan.
The doctor said it improves the blood circulation of the brain and suppress some cytokine.
Some patients have recovered dramatically, but some has had no effect.
I started to take it yesterday.

 

[Gijs]

Very interessting Hide. Did you also have a PET scan and do you have tachycardia? Let us know how it goes.

 

[Hide]

Very interessting Hide. Did you also have a PET scan and do you have tachycardia? Let us know how it goes.

I didn't have a PET and have no tachycardia.
My doctor said you would be able to test neuroinflamation by 100,000 yen (800$) soon at almost all hospitals.

 

[Gijs]

THX Hide for your reply. Does your doctor mean the same PET scan like the Japanese study which found neuro inflammation (glia activation) ?

 

[Hide]

Sorry. I don't know about the details. But I hear there are only 6 or so PET scans which can find neuro inflammation in Japan now, but by using some materials even MRI may be able to find inflammation.
I am not quite sure about it.

 

[wastwater]

Maybe leaks in Endothelial tissue lead to all these after affects,like microglial activation,might even be a protective measure.I saw that chlamydia pneumonia can have a negative impact on Endothelial tissue.

 

[CaptainA]

Yesterday I was prescribed Ibudilast by the leader of research team in Japan.
The doctor said it improves the blood circulation of the brain and suppress some cytokine.
Some patients have recovered dramatically, but some has had no effect.
I started to take it yesterday.

Hey @Hide how did the treatment go? I've been in contact with a lead researcher on this subject in US they think this could be the a viable treatment.