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Prostaglandins, rather than cytokines, central in communicating inflammation to brain

natasa778

Senior Member
Messages
1,774
Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines

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

Sub-pyrogenic inflammation resulted in changes in a species-typical, untrained behavior (burrowing) that depends on the integrity of the hippocampus. Increased expression of cytokines was observed in the periphery and selected regions of the brain which coincided with changes in behavior. However, peripheral neutralization of LPS-induced pro-inflammatory cytokines IL-1?, IL-6 and TNF-? did not abrogate the LPS-induced behavioral changes nor affect CNS cytokine synthesis. In contrast, pretreatment of mice with indomethacin completely prevented LPS-induced behavior changes, without affecting cytokine levels. Taken together, these experiments suggest a key role for prostaglandins, rather than cytokines, in communicating to the brain.


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4. Discussion

Communication between systemic infection and inflammation and the brain is well known to occur and underpins the behavioral consequences of systemic infection and inflammatory diseases (sickness behavior). In previous studies, often using severe pyrogenic systemic challenges, a key role for the cytokines IL-1?, IL-6 and TNF-? has been suggested. The present study demonstrates that systemic, low grade inflammation impacts on the brain independently of peripheral cytokine production. We have shown that sub-pyrogenic inflammation induces marked changes in immune activation, such as leukocyte mobilization, macrophage and dendritic cell activation, and increased peripheral and central cytokine production, without causing overt signs of sickness but inducing anhedonia. To our knowledge, the marked changes in cellular immune activation, especially dendritic cells, have not been addressed before in studies of sickness behavior. The effect of low dose LPS on burrowing could be reversed by pretreatment with a COX inhibitor (indomethacin), indicating a pivotal role of prostaglandins. Interestingly, indomethacin did not affect the LPS-induced peripheral or central cytokine production. Most previous studies on the biological mechanisms underlying sickness behavior have been performed under conditions using higher doses of LPS than those used here. We believe that the model described in the present paper could be particular relevant to humans, who more commonly experience sub-pyrogenic infections or inflammation, rather than septic shock.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I have been interested in this topic since 1993. Eicosanoids (not just prostaglandins) are highly disturbed in ME. Treatment based on this goes back to 1988 but there was never any real interest or funding. Look up Gray and Martinovic on PubMed. Several of the popular theories on ME including the tenth paradigm and methylation theories link to problems with cyclooxygenase and inflammatory eicosanoids.

I became interested in indomethacin very long ago when I realized that alcohol poisoning is nonlethal under indomethacin. Alcohol kills via release of arachidonic acid, which triggers cyclooxygenase activity and hence eicosanoid synthesis. It also triggers massive oxidative stress and localized vasodilation. Many of these eicosanoids are pro-inflammatory. My dietary strategies since 1993 have been aimed at reducing this kind of eicosanoid impact. I keep meaning to write a blog on this, but its still only half finished, and has been half finished for months.

Bye, Alex
 

Snow Leopard

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South Australia

anciendaze

Senior Member
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1,841
Notice that prostaglandins got their name from a gland which has figured prominently in recent debate, though the biochemicals found in the original discovery probably originated in seminal vesicles. We are still talking about chronic sub-acute inflammation of ducted glands which undergo dramatic changes at sexual maturity. The corresponding female structures are Skene's glands and the endometrium.

Someone should ask Denise O'Keefe about prostaglandins and her research on benign prostatic hypertrophy (BPH), to say nothing of reported findings of retroviruses with replication promoted by androgens and glucocorticoids.
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,074
Location
australia (brisbane)
IL6 is interesting as seems to play a big role in causing sleep issues in cfs, dhea is known to help reduce IL6. SInce using dhea at the start of the year my sleep has seemed to stabilize and although far from perfect, it has improved and i have reduced my sleep meds some. I dont take dhea as a sleeping pill before bed but in the morning as it helps with energy but helps lower IL6 which indirectly may help with sleep???

cheers!!!!
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Notice that prostaglandins got their name from a gland which has figured prominently in recent debate, though the biochemicals found in the original discovery probably originated in seminal vesicles. We are still talking about chronic sub-acute inflammation of ducted glands which undergo dramatic changes at sexual maturity. The corresponding female structures are Skene's glands and the endometrium.

Someone should ask Denise O'Keefe about prostaglandins and her research on benign prostatic hypertrophy (BPH), to say nothing of reported findings of retroviruses with replication promoted by androgens and glucocorticoids.

Hi anciendaze, I just wish to correct a potential error. Prostaglandins were historically isolated from the prostate (of bulls I think) but every single cell in the body that is metabolically active makes them. These are autocrine and paracrine hormones, not endocrine hormones. Even simple multicellular organisms make them. Prostaglandins are a subtype of eicosanoids, which refers to twenty (eicosa-) carbons. They are fat derivatives, that is fat-based hormones.

The role of autocrine hormones is to signal the originating cell - they are a way of transmitting information across a cell. Paracrine hormones are similar, but they transmit from cell to cell - they spread hormonal signals through tissues. Endocrine hormones on the other hand transmit signals via the blood. So inflammatory eicosanoid hormones have a range of only a few millimeters. However, it is possible for chain reactions to occur - one cell triggers the next, and so on. It is also probable, though I do not know to what extent it has been researched, that eicosanoids can trigger additional responses via other hormones and nerve impulses, and these can travel farther.

If you heavily rub the inside of your arm the skin goes red. This is the action of eicosanoids (and other mechanisms including histamine I think) - a rapid inflammatory response. Eicosanoids have a very short half-life typically, on the order of seconds. They are hard to isolate and study.

I hope this information is accurate, I have not researched this topic in many years.

Bye, Alex
 

Snow Leopard

Hibernating
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Notice that prostaglandins got their name from a gland which has figured prominently in recent debate, though the biochemicals found in the original discovery probably originated in seminal vesicles.

The gland doesn't have to be directly involved if we are talking about isoprostanes which are analogues of prostaglandins, but are products of "free radical-catalyzed peroxidation of essential fatty acids".

The functions of the various prostaglandins are interesting though:
http://en.wikipedia.org/wiki/Prostaglandin#Types
And for isoprostanes,
http://ajplung.physiology.org/content/280/6/L1067.full.pdf+html
 

anciendaze

Senior Member
Messages
1,841
Note that I never said prostaglandins were only produced by the prostate. I even said that the original isolation probably found chemicals produced by seminal vesicles. My point was that reproductive organs produce copious amounts which made detection easier. This is consistent with hypotheses including viruses causing inflammation having androgen and glucocorticoid receptor elements, also with a preference for mucous membranes.

At this point I won't say more.
 

natasa778

Senior Member
Messages
1,774
looks like hypobaric hypoxia-induced immune changes are also mediated by PGs. I don't have access to full paper but the claim is:

http://www.ncbi.nlm.nih.gov/pubmed/22270486

Some cell-mediated immune responses are altered in hypobaric hypoxic (HH) condition in rats. Prostaglandins (PGs) are increased in hypobaric hypoxia and non-steroidal anti-inflammatory drugs are used to facilitate acclimatization in high altitude by inhibiting PGs. The present study explores the role of PGs in hypobaric hypoxia-induced immune responses by inhibiting its synthesis with different doses of naproxen. The rats were exposed to HH condition at 18,000 ft in a simulated chamber for 8 h/day for 6 days. The phagocytic activity of circulating blood WBC, measured by fluorescein isothiocyanate-tagged bacterial cell, was increased in HH and this change was blocked after administration of naproxen. There was reduction of natural killer cell cytotoxicity of splenic mononuclear cell and delayed type of hypersensitivity responses to bovine serum albumin in rats exposed to HH condition but these immune responses were blocked after administration of naproxen in HH condition. The leukocytes adhesive inhibition index was not altered in HH condition and after administration of naproxen in HH condition. The serum corticosterone (CORT) concentration was increased in rats exposed to HH condition and this elevated CORT concentration was blocked after administration of naproxen in HH condition. The observed HH-induced immune changes are inhibited by naproxen in a dose-dependent manner. The study indicates that hypobaric hypoxia-induced immune changes are mediated by PGs.
 

natasa778

Senior Member
Messages
1,774
also this very recent one, confirms previous:

http://www.ncbi.nlm.nih.gov/pubmed/22219191

.... The results show that astrocytes respond to LPS by a COX-2-dependent production of prostanoids, mainly vasoactive PGE(2), and suggest that the coordinated down-regulation of COX-1 facilitates PGE(2) production after TLR-4 activation. These effects might induce cerebral blood flow responses to brain inflammation.