Jarred Younger on Neuroinflammation in ME/CFS and Fibromyalgia

[Jonathan Edwards]

If microglia are implicated and effective inhibitors can be found or developed, why not keep taking them?

Maybe why not. But they might have side effects and might wear off and if there is a chance that by B cell targeting you can wash the disease out completely then clearly that would make people feel happier. Nobody likes to have an illness that they will have to take medicine for for ever.

 

[user9876]

Thinking about the other current thread on rituximab it might well be useful to give inhibitors of microglial activation for a quick response and then follow up with rituximab or a newer better B cell drug to deal with longer term remission.

I assume that would make trial results harder to interpret?

 

[user9876]

Maybe why not. But they might have side effects and might wear off and if there is a chance that by B cell targeting you can wash the disease out completely then clearly that would make people feel happier. Nobody likes to have an illness that they will have to take medicine for for ever.

That suggests that there is a maintenance cycle which will keep reactivating microglia. It seems some people seem to have a long but temporary illness after an infection where as others it seems much more permanent. I guess I'm thinking some people seem to get better within a couple of years where as those who have been ill for a long time don't seem to get better although may have significant improvements.

What I was wondering is could there be two mechanisms. One where microglia activation is causes and perhaps what ever causes it sticks around maintaining it for a while but then goes. And a different mechanism where say antibodies cause microglia activation and keep being produced to maintain the activation hence the long term nature of the illness.

Would there be any way of telling?

 

[Sasha]

Microglial activation is one of the areas I think is most worthy of study. I am all for it.

I hate the term neuroinflammation though. It is a trendy buzzword that confuses everyone. This is not really inflammation in any helpful sense. It is a new type of problem that deserves its proper name - which is:

microglial activation.

What's the stuff that the Japanese are talking about? Is that microglial activation?

 

[Sasha]

Thinking about the other current thread on rituximab it might well be useful to give inhibitors of microglial activation for a quick response and then follow up with rituximab or a newer better B cell drug to deal with longer term remission.

Do such things already exist? Have any of them already been tried on/by PWME, as far as you know?

 

[Scarecrow]

Do such things already exist? Have any of them already been tried on/by PWME, as far as you know?

Younger mentioned a few in a recent talk (I'll see what I can find) - some were herbal / some pharmaceutical. Some he wouldn't name.

 

[Jonathan Edwards]

I assume that would make trial results harder to interpret?

There would need to be separate trials for the different drugs and then maybe a trial of sequential usage. I do not see serious confusion arising because I would expect microglial inhibitors to have a fairly rapid onset of action, although that might be overoptimistic.

 

[Jonathan Edwards]

That suggests that there is a maintenance cycle which will keep reactivating microglia. It seems some people seem to have a long but temporary illness after an infection where as others it seems much more permanent. I guess I'm thinking some people seem to get better within a couple of years where as those who have been ill for a long time don't seem to get better although may have significant improvements.

What I was wondering is could there be two mechanisms. One where microglia activation is causes and perhaps what ever causes it sticks around maintaining it for a while but then goes. And a different mechanism where say antibodies cause microglia activation and keep being produced to maintain the activation hence the long term nature of the illness.

Would there be any way of telling?

It could certainly be that cmplicated and unless one could tease out subsets it might make interpretation of drug usage tricky. But if Younger is trying out microglial inhibitors on their own it seems likely that any useful effects will show up that way and that combinations can be put together intelligently at a later stage.

 

[Jonathan Edwards]

What's the stuff that the Japanese are talking about? Is that microglial activation?

Yup.

 

[JPV]

Maybe why not. But they might have side effects and might wear off and if there is a chance that by B cell targeting you can wash the disease out completely then clearly that would make people feel happier. Nobody likes to have an illness that they will have to take medicine for for ever.

Are there any studies showing defective B cells are the root cause of ME/CFS?

Seems to me that defective B cells and overactive microglia are very likely a downstream symptom of whatever the root cause is. If that's the case, one would think that the newly generated B cells will eventually become defective if the root cause isn't ever addressed and corrected.

 

[JamBob]

It seems so JPV, but I dont find it it reasonable to stick ones head in the sand with two thirds responding to rtx.

Jonathan had a very interesting comment in another thread:

"There is a mechanism that we have been discussing amongst scientists in the UK interested in the potential role of B cells. Rituximab must be working by removing B cells, I think, since it really does nothing to anything else. If we think the Norwegian data indicate a real effect I think we have to take into account that this effect takes about 6 months to be fully apparent. That points strongly in the direction of the effect being through antibody production rather than some immediate effect of B cells through something like antigen presentation.

So how would blocking new antibody production over a six month period help if these were not autoantibodies? I think there is a genuine alternative possibility. The antibody that declines with six months of B cell depletion is antibody produced by short lived (mostly splenic?) plasma cells. This sort of antibody probably includes a relative high proportion of low affinity/broad specificity antibody - sort of rough and ready dirty antibody. If we postulate that ME in the chronic phase is due to a hypersensitivity of brain stem/autonomic circuits to very low level immune danger signals it might be that what generates symptoms are the normally trivial levels of cytokine or other signal that occur as part of normal daily clearance of toxic material and low grade microbes. A good part of those signals may be triggered by interactions with 'rough and ready' antibody. So if the immune system is 'flushed out' of such antibody without the ability to top it up then symptoms may improve.

We considered this idea because we needed to to think about how one might see improvement with rituximab and yet find no apparent 'abnormality' in B cells or antibody levels or specificities."

@JonathanEdwards

Hypothetically, from a theoretical point of view, in the scenario presented above, would the introduction of glucocorticoids (at low replacement-level doses) have any impact?

I just ask because before commencing low-dose steroids, I was bed bound and my condition was declining week by week, but with the gluco- & mineralcorticoids I am not bed bound (unless intercurrently ill) and have better functioning.

Would the anti-inflammatory action of glucocorticoids impact on microglial activation or is that theoretically not possible?

 

[user9876]

It could certainly be that cmplicated and unless one could tease out subsets it might make interpretation of drug usage tricky. But if Younger is trying out microglial inhibitors on their own it seems likely that any useful effects will show up that way and that combinations can be put together intelligently at a later stage.

I guess I'm wondering about the life cycle of how microglia activation would work normally and whether the timings of normal vs abnormal would tell us anything. I'm assuming that if a pathogen travels to the brain then microglia would normally activate clean up and then deactivate (or would something deactivate them).

If they fail to deactivate how long would a microglia cell live for before being replaced. But if one fails to deactivate would a drug help deactivate it say if a deactivation sensor was blocked.

If a drug treatment didn't tell work and scans before and after showed activation would that suggest the deactivation mechanism was failing? Or are we less sure how well the drugs work; or could the reactivation process work as fast as the drug based deactivation process. Could we tell the difference.

 

[Scarecrow]

@Sasha - it was the Pandora webinar embedded here.
http://forums.phoenixrising.me/index.php?threads/youngers-research-in-alabama.35153/#post-550164

At the 39 minute mark:

Pharmaceuticals
LDN
Minocycline
Ibudilast
Dextromethorphan
Rifampin
Propentofylline
Ceftriaxone
Glatiramer acetate

plus a whole bunch that are in development in animals.

Herbals
Curcumin
Resveratrol
Gastodia elata
Obovatol
Inflexin
Piper kadsura
Ganoderma lucidum
Berberine
Epimedium brevicornum
Isodon japonicas
Stephania tetrandra
Stinging nettle
Fisetin
Pycnogenol
Boswelia
Kratom

 

[Sasha]

@Sasha - it was the Pandora webinar embedded here.
http://forums.phoenixrising.me/index.php?threads/youngers-research-in-alabama.35153/#post-550164

At the 39 minute mark:

Pharmaceuticals
LDN

[...]

Herbals
Curcumin

Interesting - a lot of people have tried LDN, of course, and some report benefits (not me, unfortch ). And people have tried curcumin for its antiviral (?) properties.

 

[JPV]

Interesting - a lot of people have tried LDN, of course, and some report benefits (not me, unfortch ). And people have tried curcumin for its antiviral (?) properties.

Resveratrol, Boswellia and Pycnogenol have also been frequently discussed on the forum.

 

[Scarecrow]

a lot of people have tried LDN, of course, and some report benefits (not me, unfortch

Younger said that he had used it in fibromyalgia with great success but hadn't studied it in ME yet.

Can you say who wrote you a prescription? (PM if you would rather). I can't imagine my GP doing it but you never know.

). And people have tried curcumin for its antiviral (?) properties.

I think it's more widely known as an anti-inflammatory.

 

[Scarecrow]

Resveratrol, Boswellia and Pycnogenol have also been frequently discussed on the forum.

I noticed a Kratom thread too but haven't read it.

 

[JPV]

Can you say who wrote you a prescription? (PM if you would rather). I can't imagine my GP doing it but you never know.

Not sure if they deliver to Scotland but there are numerous websites that sell it without a prescription. Just do a Google search.

 

[Scarecrow]

Not sure if they deliver to Scotland but there are numerous websites that sell it without a prescription. Just do a Google search.

Thanks. Pretty confident I can get anything delivered except unpasteurised milk.

 

[FancyMyBlood]

Never really been a fan of phytochemicals and curcumin and resveratrol in particular have terrible bioavailability.

Interestingly I was prescribed minocycline last year and I was pretty excited to hear my GP was giving me that particular antibiotic (knew about the it's purposed microglia activation inhibitor properties), but unfortunately it had no effect at all on my ME/CFS symptoms.

But who knows what plasma levels are needed for minocycline to be an effective microglia activitation inhbitor and wether those levels can be reached with generally prescribed doses.