Chiefly because the immune system isn't inside the brain, even if sometimes it has effects on the brain.
We'd need glial modulators. I don't think there's been a lot of R&D for those. Another reason for not administering drugs directly to the brain: legal ramifications if violating the BBB causes infection.
Wait sorry I mean if it's glia, are glia the immune system in the brain? Are we talking about glia or the main immune system?
Microglia are part of the innate immune system. 'Immune suppression' is usually used to mean suppression of the adaptive immune response, although it is a fairly useless term anyway. Cells like microglia are very effectively suppressed by corticosteroids, which do little for ME. Even if glia are recruited for some sort of immune reaction in brain in ME that is almost certainly due either to some primary damage to brain that they are there to clear up - in which case suppression doesn't make sense - or to some systemic immune response outside the brain - which would be better targeted outside brain.
I read that corticosteroids can increase microglia activation. As always I'm thinking on a completely lower level haha. Thank you for explaining again I suppose then you're not a fan of the neuroinflammation camp? What if they are doing what they said but forgot to turn down or something. Having said that neuroinflammation is a non specific term isn't it. Is there any paper for corticosteroids and MR? The reason I'm asking is because J Younger said fibro is likely a central immune disorder, and I saw that regular immune suppressants don't cross the brain, so why not just send them through the spine like intrathecal. For steroids, I imagine steroids are no good for the brain side effects. Uh oh I did an oopsie. I thought neuroinflammation was a big player in cfs, but I realise now the article I saw were talking mainly only about fibro... There is no very well health page for cfs and neuroinflammation, only fibro
Are astrocytes suppressed by corticosteroids as well? Also, how effective would corticosteroids if the inflammation is getting worse at the same time as the treatment is given, ie, say DAMPS are increasing in concentration and leading to more inflammation
I don't know what the direct effect is, but astrocytes get triggered by cytokines, so reducing the level of those in the bloodstream should have some effect. Prednisone gave me temporary remission the first two times, then stopped having an effect, so I don't know what that means in terms of corticosteroids/ME theories.
Professor I was wondering your opinion on neuroinflammation, and a quick search of the forums show you're a skeptic. I know you say glia activate for all sorts of reasons. And pretty much any reason. But I'm curious what you think of neuroinflammation in regards to central sensitization, before the talk of neuroinflammation, fibromyalgia CS was talked about in regards to spinal glia activation, and then after Dr Youngers study it seems people started attributing fibromyalgia to neuroinflammation. So if we don't call it neuroinflammation, and just glia stuff r u still a skeptic One thing I'm curious about, there are different types of neuroinflammation aren't there? Otherwise why don't other neuroinflammatory conditions cause CWP, like TBI
The involvement of spinal glia in sensitivity to pain comes from rat experiments. People with fibromyalgia show 'central sensitisation' in the sense that they seem more sensitive to stimuli for reasons that appear to be central but I don't think anyone has any good evidence that glial activation is involved in humans. As you say, glial activation occurs with stroke, Alzheimer's, Parkinson's, multiple sclerosis you name it and doesn't particularly lead to central sensitisation. I don't actually think anyone has got anywhere with this. The animal models of glial activation are almost certainly irrelevant. I doubt Jarred Younger's claims are taken much notice of by neuroscientists in this field either. It is all empty talk. Unfortunately there is an increasing tendency for the received wisdom in science, in terms of what gets talked about at meetings, to be based on these vague buzzwords. Real science has to be specific.
Hip Would it even be possible to find evidence for this? Given that glial activation is non specific right? So you would have a hard time ever proving causality? But what if glia activation is actually relevant, but, it's not specific. If you open a dead persons body, they will have glia activation all over isn't that right? I read that glia activate when oxygen is low. Is it an unverifiable theory? There's no way we can use human subjects to verify, so if animals are like that, can we say good enough? If I had the same evidence requirements as you, I'd say even if we ran a trial of a drug for neuroinflammation and it's successful, you'd say that how can you be sure that is the mechanisms by which it works right? For eg naltrexone. If we run minocycline, ibudilast trials bc they're known to be 'neuroprotective' or glial modulators. But they also have other roles too. Or, if we inject corticosteroids centrally and they help, can we say muabe there was inflammation, or we we inject cytokine inhbitiros. Be cause this rationale was used to say fibromyalgia is not inflammatory, when they ran prednisone trial. Can we use the opposite rationale or is that not good enough, even if trial says yes it works even if we can't prove that it was this happening Otherwise how could we ever prove that glia is involved in human pain? Or prove it is not. I cannot think of any ways because I am no scientist In regards to other neuroinflammation conditions, in a paper I read, the author says that CS can happen without peripheral input as a result of changes to the CNS, and this happens in MS. And for stroke, they get pain too, and parkinson's too pain but I don't think they get CWP a lot right. But at least it's possible. ALS People do experience pain too. I just read for stroke if pain perception part if affected then yes, they ll get pain. Thus, location plays a role oerhaps in determining who gets CWP or CS and who does not. Also I realised given that they can develop CWP, but neuroinflammation is a non specific thing can is it even fair to compare any 2 neuroinflammation? Because we are talking of vague things? If we don't really measure neuroinflammation in fms, are we even getting measurements in pd or Ms? For neuroinflammation? All the neuroinflammation disorders they ate also poorly understood as well aren't they. So we're comparing bliynd yo the blind And, how about the molecular mechanisms proposed for neuroinflammation? At least those are sound surely? That post synaptic neurons have receptors for all sorts of inflammatory molecules? And that these can turn them on. In summary I see a lot of possibilities but no way to confirm, it seems likes it possible but difficult to have any concrete proof without yknow ethical problems On another note what Bout the theory all pain is inflammation. Clearly, it is not all, as you got phantom limb pain and ppl experiencing pain out of the blue, but most pain seems related to inflammation at the molecular level is that right? Nociception Also, do we have any other alternative explanations that are not rooted in psychology? Or psychiatry? There seem to be only a few suspects if it is central, glia, epithelial, maybe surveilling immune cells from the rest of the body, the neurons themselves. Glia seem like the easy target, but all these cells are capable of producing inflammatory garbage so...
On a personal note, I just wNt to add my own ane dote. I have fibro with PEM same as cfs, meaning I can get permanently worse. And. I have been doing so for the past 5 years, though without knowing it bc I used to push myself rest later. Turns out I was slowly getting worse when I thought I was sliding sideways. 1year ago, suddenly implying reading made me detoriate, and I the weeks before that I had a blood test one of which was CRP. I'd done a few before those and they were all at one. This test returned a 2. I didn't think much of it normal fluctuations I thought. Fast forward a few months and then it's 3 and then it's 4. Maybe it's because I got fatter. But this trend started before I crashed. Add that to ldn helping me twice in 1 dose, and marijuana for some reason caused me to have a 'crash' in baseline activity that I have yet to recover. I've tried prednisone not long b4 LDN and marijuana for apparently unrelated problems. Prednisone was just by luck, I was interested to see if I really had fibromyalgia in the same way so I wanted to see if findings on fibromyalgia would be similar to me because at that pt I thought I had CFS bc I had PEM. Because prednisone did not do anything, I think I can safely say there is nothing peripherally happening to me, yet my CRP remains up. And because prednisone did nothing, I must assume whatever marijuana was doing to me to make me worse was central. Yet marijuana is known to have anti inflammatory properties, but if you Google it, you'll find people who complain it makes their pain worse. Cb1 receptor has dual pro and anti inflammatory properties, and, i took full spectrum cbd with only a tiny amount of thc. So it's possible there's another offending substance. Anandamide elicited nitric oxide (NO) release in human monocytes [94], rat median eminence fragments [95], human saphenous vein segments [96], and cultured human en- dothelial cells[97,98]. Antagonism by SR141716 suggested that this response was mediated by CB1 receptors, and antagonism by (L)-N-arg-methyl ester (L-NAME) implicated an iso- form of nitric oxide synthase (NOS). In cultured human endothelial cells, NO generation was preceded by a rapid increase in intracellular Ca2+ concentration [97,98], consistent with the stimulation of a Ca2+-regulated constitutive NOS. In saphenous vein endothelia, an influx from the extracellular Ca2+ pool was required for NOS activation [96]. https://pubmed.ncbi.nlm.nih.gov/12432948/ NOS can directly cause pain by activating. Wait hold on I may be confused it looks like NOS is pain relieving. I thought it was involved in nociception. Wait I remember, NOS means oxidative stress equals DAMPS means more inflammation! Means more pain I have a strong vested interest in neuroinflammation as a cause of fibromyalgia. I wonder, it is a plausible explanation right? It could be an explanation for everything. But there is no solid evidence, and I doubt you can ever have such a thing if its non specific and inside the brain unless you find that treatment works. Bloody hell though if u Google all the clinical trials on fibro registered to the US website, there are no treatments specifically aimed at neuroinflammation. Most of them are exercise trials
Wait sorry this is an important q so I'll make it a single post, central sensitization is not the same as central pain is it?
Uh I had a realisation that there are immune suppressants given intrathecally, for leukemia! Intrathecal methexotrate. And... As with rituximab and lymphoma, some leukemia patients outta have cfs or fms. But no one has reported anything so ig eh. Methexotrate may have anti il one propertied
Oh nevermind, mtx activates microglia and astrocytes. Intrathecal steroids are given for cancer too? But, steroids also activate glia...
On another note, anybody know why neuroinflammation conditions are not treated as inflammatory conditions? Eg the neuro degenerative ones https://pubmed.ncbi.nlm.nih.gov/28499701/#:~:text=We argue that a problem,'glia' could be obsolete. Says they've all failed but they haven't done much intrathecal stuff They are seen as NIND. NON INFLAMMATORY NEUROLOGICAL DISORDERS, but with neuroinflammation
What do you think of intrathecal il ten gene therapy? It looks like there are gonna be clinical trials of this soon. There was a clinical trial but it got cancelled. Xt-150 If this works, and fibro/cfs is neuroinflammation, then great we have something in the pipeline!!! https://clinicaltrials.gov/study/NCT04466410?cond=Neuropathic Pain&intr=Intrathecal gene&rank=1
