Could prostaglandins be the key (for some PWCs)?

http://www.sciencedirect.com/science/article/pii/S0889159107000359

anyone using indomethacin?

Hi Natasa, very interesting article. It would be great to know if some PWC has used indomethacin. I swear, that I saw your post afterwards but I came over another study yesterday, which looked at how prostaglandin E2 produces fever in the brain. I was searching for endothelial cells and their connection to IBD but this study was returned, which looked at the brain.


http://www.ncbi.nlm.nih.gov/pubmed?term= 22872578

2012 Aug 7. [Epub ahead of print]
Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells.


Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.

PMID:22872578[PubMed - as supplied by publisher]

This is the model of CFS I have been working with since 1993. It was first proposed by Dr Andriya Martinovic in the late 1980s, and I was one of the guinea pigs. Its interesting that indomethacin also halts death from alcohol poisoning (from memory, hope I am not confusing it with another drug). This all ties in with many of the existing models of CFS and ME from Pall's peroxynitrite, to more recent autoimmune, and even methylation. Its all connected.

By manipulating these pathways through diet not drugs, Dr. Martinovic was able to subtantially reverse symptoms in 60% of patients, though about ten percent got worse and thirty percent had limited improvement - that included me.

http://www.ncbi.nlm.nih.gov/pubmed?term=cfs martinovic

This is one of about five papers, but I think the only one indexed on Pubmed. This model has substantially influenced my thinking to the current day. The thing is that it is very compatible with many modern models.

COX-2 issues also tie in with salicylate sensitivity.

Those case histories mentioned, good chance one of them was me.

Bye, Alex

PS See also: http://arthritis.emedtv.com/indomethacin/indomethacin-uses.html

I thought I would add something since it has not been mentioned on this thread. The conclusion that it must be prostaglandins might be wrong. This is because the pathway that is blocked produces a whole family of hormones called eicosanoids. One branch of that family is prostaglandins. So it might be premature to presume it is prostaglandins rather than some of the other eicosanoids, though of course it could be prostaglandins in combination with other eicosanoids.

It is unclear how the knockout mice study shows otherwise. I suspect PGE2 is a intermediate chemical on the way to other things, not just an end product. However this does indicate the primary problem is possibly series 2 eicosanoids (thats what the 2 on the end means, its a family of hormones, second of three families). The substrate for these hormones is omega-6 polyunsaturated fats.

Everyone should be aware that indomethacin has been used to treat CFS, but I am unsure it was that successful. Also, its potentially a dangerous anti-inflammatory.

Bye, Alex

Curcumin might be of interest:

Curcumin blocks prostaglandin E2 biosynthesis through direct
inhibition of the microsomal prostaglandin E2 synthase-1

Most treatments to block PGE2 have focussed on blocking arachidonic acid metabolism, the substrate for PGE2, typically by targeting cyclooxygenase but not always (aspirin, fish oil etc). If curcumin is effective that would be better, as it would allow other eicosanoids to be synthesized. However, we have a major increase in arachidonic acid metabolism. This is due to both NFkB and NO, but there may be other factors as well. Alcohol poisoning is thought to cause death by a massive release of arachidonic acid. Even a small increase in arachidonic acid in animals can cause sudden death. Its because free arachidonic acid is made into hormones, and many are highly inflammatory.

Arachidonic acid release also causes an oxidative burst from mitochondria, but back when I was reading on this the mechanism was not known, it was an empirical finding in reperfusion injury research.

Bye, Alex

Another interesting supplement/drug is lithium:

Chronic lithium administration attenuates up-regulated brain arachidonic acid metabolism in a rat model of neuroinflammation.

It might also be fruitful to look into phospholipase inhibitors:

Inhibitors of Brain Phospholipase A2Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

One such compound that I like, is CDP-choline. Besides decreasing phospholipase A2 activity, it also increases membrane fluidity, increases gluthatione, and increases dopamine receptor densities in the striatum. Dopaminergic activity here has been found to be low in ME. Vitamin E is another compound.

and quercetin, which IIRC inhibits not only release but also synthesis