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"The Most Powerful Somnogen Known To Man"

wakefulness energy prostaglandin pgd2 inflammation

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#1 Pereise1

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Posted 24 July 2017 - 07:36 PM


So after scouring Pubmed for a link between sleepiness and inflammation, I found the following:

 

Prostaglandin (PG) D2 is the most potent endogenous sleep-promoting substance. PGD2 is produced by lipocalin-type PGD synthase localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain, and is secreted into the cerebrospinal fluid as a sleep hormone. PGD2 stimulates DP1 receptors localized in the leptomeninges under the basal forebrain and the hypothalamus. As a consequence, adenosine is released as a paracrine sleep-promoting molecule to activate adenosine A2A receptor-expressing sleep-promoting neurons and to inhibit adenosine A1 receptor-possessing arousal neurons. PGD2 activates a center of non-rapid eye movement (NREM) sleep regulation in the ventrolateral preoptic area, probably mediated by adenosine signaling, which activation inhibits the histaminergic arousal center in the tuberomammillary nucleus via descending GABAergic and galaninergic projections. The administration of a lipocalin-type PGD synthase inhibitor (SeCl4), DP1 antagonist (ONO-4127Na) or adenosine A2A receptor antagonist (caffeine) suppresses both NREM and rapid eye movement (REM) sleep, indicating that the PGD2-adenosine system is crucial for the maintenance of physiological sleep.

 

Now from what I understand, Prostaglandin D2 is actually an inflammatory factor/hormone which is synthesized from Prostaglandin H2, the major prostaglandin precursor. It’s one of the major forms of inflammation created when Arachidonic acid is converted by COX-2 to all sorts of fun stuff. This is a normal reaction that occurs every night in healthy/nonhealthy people by which wakefulness is decreased and sleep is induced.

 

Well, it’s well known that wakefulness and sleep is a sort of a pendulum or see-saw between the lateral hypothalamus and the ventrolateral preoptic nucleus (VLPO) in the anterior hypothalamus. For an illustrated model, consult this image. Orexin is thought to promote wakefulness by activating the Tuberomamillary nucleus (TMN). It also activates the dorsal raphe nucleus (serotonin) and the locus coeruleus (norepinephrine). These areas of the brain then inhibit the VLPO, although orexin may directly do this as well. How does Prostaglandin D2 come into play? Well, PGD2 activates the VLPO (http://www.pnas.org/content/95/13/7754). It does this more strongly than either adenosine or serotonin which are the other two main activators of the VLPO. This is why one can have massive amounts of caffeine, one of the strongest adenosine antagonists, and still feel sleepy.

 

So theoretically, antagonizing PGD2 should have the effect of strongly increasing wakefulness without interfering with the normal, circadian sleep inducing effects of serotonin and adenosine. At least, that's what the following study using a PGD2 receptor antagonist seems to imply:

 

We infused this DP1 antagonist into the subarachnoid space underlying the rostral basal forebrain of rats during their sleep period. ONO-4127Na infusion at 50 pmol/min had little effect on the sleep-stage distribution. However, ONO-4127Na given at 100 and 200 pmol/min reduced NREM sleep by 23 and 28%, respectively, and REM sleep by 49 and 63%, respectively, during perfusion for 6 h and postinfusion for 1 h. As shown in Fig. 5, ONO-4127Na infusion at 200 pmol/min decreased the amount of NREM sleep over a 7-h period by 30–40%, and reduced REM sleep by 60–90% commencing about 2 h after the beginning of ONO-4 127Na infusion, as compared with the baseline.

 

 

 

 

So far, for PGD2 inhibitors, I've only been able to find the following:

 

Fish Oil (DHA/EPA):
 
Feverfew (Non-COX pathway):
Feverfew: A systematic review (Scroll down to the Anti-inflammatory section)
 
Vitamin K2 MK-4 (Through inhibiting the precursor Prostaglandin):
 
So far, it seems that lowering COX-2 and favoring a higher Omega-3:Omega-6 ratio seem to have the most evidence. So for those interested in assisting in the search for a good inhibitor for general wakefulness:
 
PGD2 produced by L-PGDS, not H-PGDS
Inhibition of the DP1 receptor, not DP2
 

 

On the flip side, anything that increases PGD2 would theoretically help with sleep onset in those who have insomnia. After all, it seems to be the most powerful inducer of sleep among anything endogenous. I haven't seen much talk about it so I thought it'd make a good research area for life enhancement!

 

Edit: fixed links


Edited by Pereise1, 24 July 2017 - 07:39 PM.

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#2 Pereise1

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Posted 26 July 2017 - 01:22 AM

Well, seems that green soybeans increase L-PGDS, which would help for insomnia as well as Alzheimer's:

 

 
4. Discussion

Aβ is constantly produced from its precursor and immediately catabolized under normal conditions, whereas dysmetabolism of Aβ seems to lead to pathological deposition upon aging (Saido, 2013). Besides the correction of Aβ-dysmetabolism, an increase of endogenous Aβ-chaperone should lead to suppression of Aβ-induced neuronal dysfunction,resulting in prevention of cognitive dysfunction. Ptgds being a major endogenous Aβ-chaperone in the brain (Kanekiyo et al., 2007), it may be possible that increased Ptgds expression is a key factor for the beneficial effect of green soybean on cognitive function.

In brain parenchyma, Ptgds is mainly expressed in oligodendrocytes (Urade et al., 1993), and the expression of Ptgds is regulated by estradiol directly and indirectly (Devidze, Fujimori, Urade, Pfaff, & Mong, 2010; Mong et al., 2003). Soy isoflavones (genistein and daizein) and the metabolite, equol, bind to estrogen receptors (ER α/β) with higher affinity than 17β-estradiol (Adams, Aksenova, Aksenov, Mactutus, & Booze, 2012; Jiang et al., 2013), suggesting that green soybean isoflavones may activate transcription of Ptgds through binding of ER to estrogen response elements. Suppression of aging-dependent accumulation of Aβ by ingestion of dietary foods is an important strategy for prevention of cognitive dysfunction. Green soybean may be a good candidate for the suppression of Aβ accumulation.

 

 

I'm personally more on the lookout for antagonists but I suppose this might help someone out there.



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#3 Pereise1

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Posted 26 July 2017 - 06:18 PM

I enjoyed the following review titled Prostaglandin D2 and sleep/wake regulation:

 

 

Practice points

  • PGD2 is the most potent endogenous sleep-promoting substance thus far reported.
  • PGD2 is involved in the regulation of physiological sleep.
  • PGD2 is produced by lipocalin-type PGD synthase dominantly localized in the leptomeninges and secreted into CSF as a sleep hormone.
  • PGD2 activates DP1 receptors dominantly localized in the leptomeninges from the basal forebrain to the hypothalamus and increases extracellular adenosine, which diffuses into the brain parenchyma as the secondary somnogen. R

 

 

I'm highly curious if PGD2 produced by Monoacylglycerol lipase, which degrades the endocannabinoid 2-AG into arachidonic acid, is also involved in daytime sleepiness by those with neuroinflammation or infection. Considering both TNF-a and IL-1b potently silence orexin and the TMN, it'd make sense that heightened PGD2 mediated inflammation would be a good target for quality of life improvement.

 


Edited by Pereise1, 26 July 2017 - 06:19 PM.

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#4 Pereise1

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Posted 01 August 2017 - 06:31 PM

Seems that a combination of Scutellaria baicalensis (Chinese/Baikal Skullcap) and Eleutherococcus senticosus (Siberian Ginseng) would help, although I can't say for sure if this is L-PGDS or H-PGDS (Mast cell mediated). In either case:

 

 

Evid Based Complement Alternat Med. 2012;2012:673145. Epub 2012 Jan 5.
A Herbal Composition of Scutellaria baicalensis and Eleutherococcus senticosus Shows Potent Anti-Inflammatory Effects in an Ex Vivo Human Mucosal Tissue Model.

Zhang NVan Crombruggen KHoltappels GBachert C.
Source

Department of Oto-Rhino-Laryngology, Upper Airway Research Laboratory (URL), Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.

Abstract

Background. Patients seek an effective alternative to pharmacotherapy including herbal treatment options for allergic rhinitis and rhinosinusitis. Material and Methods. Nasal mucosal tissue was obtained from 12 patients, fragmented, preincubated with tissue culture medium, S. baicalensis and/or E. senticosus and/or vitamin C (each compound 0.2 μg/mL and 2 μg/mL) for 1 hour at 37°C/5% CO2, and stimulated with anti-IgE for 30 minutes and 6 hours to imitate the allergic early and late phases. Furthermore, Staphylococcus aureus superantigen B (SEB) stimulation for 6 hours was used to imitate T-cell activation.

 

Results. The combination of S. baicalensis and E. senticosus had a more potent suppressive effect on the release of PGD2, histamine, and IL-5 than S. baicalensis alone. The combination also resulted in a significant inhibition of SEB-induced cytokines comparable or superior to an established topical corticosteroid, fluticasone propionate. Vitamin C increased ciliary beat frequency, but had no anti-inflammatory effects. Discussion. The combination of S. baicalensis and E. senticosus may be able to significantly block allergic early-and late-phase mediators and substantially suppress the release of proinflammatory, and Th1-, Th2-, and Th17-derived cytokines.

 

 


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#5 CarlSagan

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Posted 14 May 2021 - 12:12 PM

another interesting approach. I will try feverfew & look for potential COX inhibitors that impact prostaglandin d2.  another study on mk4 https://pubmed.ncbi....ih.gov/8511981/


Edited by CarlSagan, 14 May 2021 - 12:41 PM.


#6 CarlSagan

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Posted 14 May 2021 - 03:34 PM

https://pubmed.ncbi....h.gov/26456343/
In silico simulations have predicted the following as potential inhibitors of PGD2 synthase:[9]

  • Ricinoleic acid
  • Acteoside
  • Amentoflavone
  • Rutin
  • Hinokiflavone

    Conclusions: Overall, ricinoleic acid, acteoside, amentoflavone, quercetin-3-O-rutinoside and hinokiflavone were predicted to be PTGDS inhibitors with good pharmacokinetic properties and minimal adverse skin reactions. These compounds have the highest potential for further in vitro and in vivo investigation with the aim of developing safe and high-efficacy hair loss treatment.

Some compounds to investigate


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#7 CarlSagan

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Posted 16 May 2021 - 01:37 PM

targeting COX-2 inhibitors long term might not be the best option as it can have negative cardiac effects (as prostacyclin is also involved with COX-2 which can be beneficial). 

 

but a drug duel targeting COX-2/5-LOX showed the same efficacy as an NSAID with less side effects over 52 weeks in osteoarthritis patients, according to -> https://www.clinical...cts/licofelone/

Later studies indicate that licofelone suppresses PGE2 formation by inhibiting mPGES-1, in addition to inhibition of COX-1 and COX-2.43 Our studies in this direction have resulted in the isolation of a natural product, chebulagic acid isolated from Terminalia chebula and 6-hydroxy salvinolone isolated from the roots of Premna integrifolia with COX-2/5-LOX dual inhibition and with potent anti-inflammatory and anticancer effects.44–46 

https://www.dovepres...ext-article-JIR

^ was initially looking into these but they are PGE2 inhibitors, and PGE2 is involved in WAKEFULLNESS as a counter to PGD2 (Sleep-Wake Regulation by Prostaglandins D2 and E2 https://pdf.scienced...80731/main.pdf)

so I wonder if looking to increase PGE2 would be another good option. directly looking for L-PGDS / H-PGDS inhibitors would be the most direct mechanism for lessening PGd2 if any are available, to lessen the general conversion process into Prostaglandin d2.

I wonder why the OP says NOT h-PGDS though?
I read in this mice study: https://www.pnas.org...t/103/47/17949 
SeCl4 inhibited sleep in WT mice, concomitant with a reduction in the PGD2 content in the brain. The sleep inhibition was also observed in H-PGDS KO mice, but not in L-PGDS, HL-PGDS double or DP1R KO mice. We conclude that PGD2 is not only involved in the homeostatic regulation of sleep but also essential for the initiation and maintenance of normal circadian sleep under physiological conditions.
 

edit: Ok seems L-PGDS is more for the brain & H-PGDS is more involved in immune / inflammation cells in tissues. but odd outcome of the mice study then, unless it's different in humans or there's more to H-PGDS than is commonly written.

 


Edited by CarlSagan, 16 May 2021 - 02:13 PM.


#8 CarlSagan

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Posted 16 May 2021 - 06:26 PM

 

https://pubmed.ncbi....h.gov/26456343/
In silico simulations have predicted the following as potential inhibitors of PGD2 synthase:[9]

  • Ricinoleic acid
  • Acteoside
  • Amentoflavone
  • Rutin
  • Hinokiflavone

    Conclusions: Overall, ricinoleic acid, acteoside, amentoflavone, quercetin-3-O-rutinoside and hinokiflavone were predicted to be PTGDS inhibitors with good pharmacokinetic properties and minimal adverse skin reactions. These compounds have the highest potential for further in vitro and in vivo investigation with the aim of developing safe and high-efficacy hair loss treatment.

Some compounds to investigate

 

The problem i'm finding is a lot of things inhibit PGE2 as well, which may have an important role in wakefulness. they have countering roles in a couple areas. unless the PGD2 inhibition is greater than the PGE2 but it's hard to find info this specific. maybe inhibiting both could still work if PGD2 is more potent

1st day I tried 100mg Feverfew, and 2nd day 300mg Feverfew. had no beneficial effects on wakefulness / excessive daytime sleepiness so far. works in the body for migraines at 100mg + i believe. (i read this impacts PGE2 too). but it may be a decent anti-inflammatory to have anyway.

Cetirizine (Zyrtec) 20mg might decrease PGD2 while increasing PGE2, but not sure if enough crosses the BBB as it's new gen, and if it does would impact on other receptors interfere. probably will try this 



#9 CarlSagan

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Posted 21 May 2021 - 11:26 AM

OK Cetirizine 20mg is a no go, as should probably be expected but was curious anyway. worsened sleepiness & came with some cognitive / motor impairment as a bonus which lasted a while. haven't found anything else that looks promising yet.



#10 CarlSagan

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Posted 29 May 2021 - 12:39 PM

I came across this thread on reversing hair loss which seems to make sense, https://www.longecit...andin-protocol/

 

they aim to lower PGD2 and increase PGE2 without inhibiting both together. one of the main things mentioned is a drug called Setipiprant. It indirectly targets PGD2 selectively by antagonizing the CRTH2 receptor. but on further look this receptor is actually the DP2 receptor.

 

as mentioned in the OP the DP1 receptor is the target as this is what PGD2 activates in the brain to increase adenosine, so i don't know if this would be helpful for daytime sleepiness being DP2? though this https://www.ncbi.nlm...ooks/NBK299187/ mentions  " DP2 is widely expressed in the brain" so i wonder about the outcomes of blocking this receptor too.

still looking



#11 CarlSagan

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Posted 31 May 2021 - 12:47 PM

https://pubmed.ncbi....v/9223656/#_=_ 

 

 

Vitamin E succinate (in melanoma cells, so its a stretch) increased PGE2 at 7-10 microg/ml while simultaneously decreasing PGD2 at 3-10 microg/ml. but no way to translate that into human dose or way to know if it would have the same impact in the brain. 

vitamin e has shown efficacy for hair regrowth for more than 30% growth over 8 months compared to placebo, which points to the pge2 increase / pgd2 increase working in practice for hair cells after oral intake https://www.ncbi.nlm...es/PMC3819075/ 

not much else to go by on if this would work for wakefulness purposes for people with excessive pgd2 in the brain but I will try this.


Edited by CarlSagan, 31 May 2021 - 01:02 PM.


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#12 sub7

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Posted 03 June 2021 - 09:34 AM

Modafinil is available and tested. Would the goal here be to find something that is even more effective in keeping one awake?
Or is there a particular side effect associated with modafinil that you are trying to avoid? 
What would be the goal here.

 

On a related note:
Orexin antagonists have recently hit the market as sleep aids (ex:Suvorexant). An agonist of orexin receptors would not only keep one awake, but also (potentially) boost metabolism in favorable fashion. Have you explored that avenue?
I myself suffer from insomnia and would be interested in an orexin antagonist. Unfortunately Suvorexant has not yet been approved where I live. I have looked all over for another orexin antagonist, but cannot find any at all. If anyone happens to think of anything, please do share....







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