Index General Discussion The Science of N Inflammation and The Most Potent Sleep Promoting Substance

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  • #1752
    Pereise1Pereise1
    Participant

    So I’ve been digging deep into the science and mechanics of sleep and wakefulness, and I’ve happened upon something that highly piqued my interest. It’s well know that elevated inflammation is bad for people with Narcolepsy, as inflammatory cytokines such as TNF-a, IL-6, and IL-1B induce sleepiness and downregulate orexin expression (Just one example). However, the mechanisms behind all this eluded me, so after much research, I present the most potent sleep inducing substance know to man:

    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 you may be wondering, what does my prostate have to do with EDS? Well, 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.

    Many think of melatonin as the end all, be all of sleep regulation. However, melatonin is simply one of 15 different factors involved in promoting sleep, and has a bigger role as an antioxidant which then preps up for sleep by clearing catecholamine metabolites built up during the day. However, that EDS? Yeah that’s Prostaglandin D2 (PGD2). How can we say that with certainty?

    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. However, what happens if you take orexin out of the picture? The VLPO overpowers the TMN, the main wakefulness center of the brain, and causes circadian problems as well as EDS.

    How does Prostaglandin D2 come into play? Well, 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. In addition, and this is merely conjecture on my part, but as PWN more than likely have elevated brain inflammation from hypothalamic glial scarring, it would only make sense that there’s more than enough PGD2 to go around! This would give a reason as to why several PWN had commented that the most awake and normal they’ve felt since becoming ill was on prednisone, an immunosuppressive steroid.

    Now, how is this directly pertinent to Narcolepsy? I’ll go ahead and quote from the Narcolepsy (2011) book by Emmanuel Mignot et. al:

    The PGD2-induced sleep was significant with as little as picomolar quantities per minute and indistinguishable from physiological sleep as judged by several electrophysiological and behavioral criteria. During the PGD2 infusion, the rats were easily aroused by the sound of a clap; and their sleep was episodic, indicating that PGD2 does not interfere with the minimum waking time for their survival. Essentially, the same sleep induction was demonstrated in the rhesus monkey Macaca mulatta during the i.c.v. infusion of PGD2. (…) The serum L-PGDS/b-trace (synthesizing enzyme for PGD2) concentration shows a circadian change with a nocturnal increase that is suppressed during total sleep deprivation but is not affected by deprivation of REM sleep

    Sound familiar? Strongly induces sleep but doesn’t contribute to restful sleep. What’s more, it seems that PGD2 is more important to the induction of REM as opposed to sleep in general, judging by the effects of a DP1 antagonist (binding site for PGD2):

    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.

    And for those wondering, yes, they have done studies on the PGD2 levels in PWN:

    Results

    In narcoleptic patients, markedly increased baseline L–PGDS levels were significantly correlated with the ESS score, but not with the degree of cataplexy. Serum L–PGDS concentrations in patients as well as in controls followed a time–dependent fluctuation with evening increases, highest values during the night and in the morning. Compared with controls, patients exhibited significant/increased amplitude of circulating L–PGDS without any suppression by total sleep deprivation.

    Conclusion

    These findings indicate that the prostaglandin–D–system contributes to the pathophysiology of narcolepsy, e. g. the regulation of excessive daytime sleepiness. Since it has been suggested that L–PGDS is also involved in neurodegenerative disorders, there may be a more specific role of the prostaglandin– D–system in narcoleptic aetiogenesis. Moreover, its linkage with the immune system as well as with human sleep regulation offers a direct access for investigating both systems.

    Therefore, with this in mind, lowering daytime levels of PGD2 should be a big priority to combat EDS in PWN. How can we do so? Well, I’m still in the process of investigating that at the moment, but I figured I might as well post the link between this important discovery and the severity of our symptoms. More to come.

    #1832
    narcolepsysupport_adminnarcolepsysupport_admin
    Keymaster

    Interesting stuff. I think I’ll need to reread a few times in order to fully absorb it, but thanks for the post!

    #1834
    FerretFerret
    Moderator

    Interesting stuff. I think I’ll need to reread a few times in order to fully absorb it, but thanks for the post!

    I’ve read it three times. Still scratching my head and hoping that the second installment will help.
    The only thing I’ve read about PGD2 is that increased levels are implicated in baldness and thinning hair.
    Then again, hormonal relationships in the body are, uh, complicated.

    #2106
    Pereise1Pereise1
    Participant

    Interesting stuff. I think I’ll need to reread a few times in order to fully absorb it, but thanks for the post!

    I’ve read it three times. Still scratching my head and hoping that the second installment will help.
    The only thing I’ve read about PGD2 is that increased levels are implicated in baldness and thinning hair.
    Then again, hormonal relationships in the body are, uh, complicated.

    Well, to summarize the important bits, PGD2 is an inflammatory factor/hormone released by mast cells and separately in the brain. It activates the sleep center (VLPO) more powerfully than any other endogenous substance or hormone. PWN have high levels of PGD2 in the brain, contributing to EDS. Therefore, instead of trying to accelerate with the parking brake on (PGD2), a good approach would be antagonizing the sleep center through antagonizing CNS PGD2 and then applying a lighter dose of some CNS stimulant of choice. Not doing so would continue the endless cycle of thought stimulation (hey there adderall!) without an equal stimulation in wakefulness.

    This is similar to the idea of lowering GABA to increase wakefulness. Problem is, GABA is necessary to prevent anxiety and exitotoxicity from all the stimulants they throw at us. Therefore, lowering PGD2 seems to be a far more effective way of inhibiting the sleep center of the brain during the time that it should be inhibited (daytime). So while PGD2 is implicated in hair loss, the function is completely different in the brain. Hair loss caused by elevated PGD2 seems to be exclusively from Omega 6 fatty acids and not from PGD2 synthesized from Omega 3. The receptor involved in sleepiness is the Prostaglandin D2 1 receptor (DP1) while PGD2 mainly causes hair loss through the DP2 receptor.

    So yes, this is far more complicated than I anticipated, but good information is out there, and the beneficial effects on N/EDS make the research more than worth it. So in the meantime, here’s a few supplements that should help lower PGD2 levels, not too sure on the dosage but I’ve been looking specifically for things that should lower EDS and brain fog:

    Fish Oil (DHA/EPA):
    Prostaglandin synthesis in rat brain astrocytes is under the control of the n-3 docosahexaenoic acid
    Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells

    Feverfew (Non-COX pathway):
    Feverfew: A systematic review (Scroll down to the Anti-inflammatory section)

    Vitamin K2 MK-4 (Through inhibiting the precursor Prostaglandin):
    Vitamin K2 (menatetrenone) inhibits prostaglandin synthesis in cultured human osteoblast-like periosteal cells by inhibiting prostaglandin H synthase activity

    I’m still trying to find more, this is an exceedingly complicated field but I’m hoping to find more. In general, 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:

    PGD2 produced by L-PGDS, not H-PGDS
    Inhibition of the DP1 receptor, not DP2

    That’s all I got for now.

    #4012
    Avatarsleeepyhead
    Participant

    I did not understand most of this. Maybe I’ll try to reread another time. But I think mct oil is supposed to have a better ratio of omega 3:6.

    #4035
    JasonJason
    Keymaster

    @pereise1 ever looked into etifoxine? Seems to be a potential inflammation reducing substance for the CNS. It’s indicated for anxiety in Europe. It and similar substance have shown promising results for the treatment of MS, nerve repair, etc. It’s also supposedly more effective than benzos for anxiety. I’m thinking about trying it as a hypnotic.

    #4314
    Pereise1Pereise1
    Participant

    @pereise1 ever looked into etifoxine? Seems to be a potential inflammation reducing substance for the CNS. It’s indicated for anxiety in Europe. It and similar substance have shown promising results for the treatment of MS, nerve repair, etc. It’s also supposedly more effective than benzos for anxiety. I’m thinking about trying it as a hypnotic.

    Hey sorry for the ridiculous delay in responding. All I could find about Etifoxine is that it “Unlike benzodiazepines, etifoxine appears to produce its anxiolytic effects by binding to β2 and β3 subunits of the GABAA receptor complex”. I’m not quite sure what the implications of that are, although I tried looking it up and it’s still a little beyond the level of research I can understand. But the peripheral benzo agonist properties vs the CNS affinity of other anxiolytics seems to be involved in avoiding tolerance, which is always good. Let me know how you like it!

    #4316
    FerretFerret
    Moderator

    Or you could try a pure CBD (cannabidiol) oil. Non toxic, anti-inflammatory and good for anxiety. Have a friend who swears by it.

    #4473
    JasonJason
    Keymaster

    @ferret my state is backwards so that isn’t an option for me!

    @pereise supposedly it primarily works as a tspo agonist and increasing neurosteroids that positively modulate GABAa receptors, reduce inflammation and enhance neurogenesis.

    #5229
    Pereise1Pereise1
    Participant

    Hey @Jason, I got the chance to try Etixofine online. It was good at being relaxing but I’m not quite sure how much it helped my sleep. It seems to need a higher dose than the pills I got for what it’s worth.

    As an aside, here’s an interesting study with a Prostaglandin D2 antagonist:

    Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice

    We therefore evaluated the wake-promoting effects of ONO-4127Na, a DP1 antagonist, in a mouse model of narcolepsy (i.e., orexin/ataxin-3 transgenic mice) and compared those to effects of modafinil. ONO-4127Na perfused in the basal forebrain (BF) area potently promoted wakefulness in both wild type and narcoleptic mice, and the wake-promoting effects of ONO-4127Na at 2.93 × 10−4 M roughly corresponded to those of modafinil at 100 mg/kg (p.o.).

    #5239
    JasonJason
    Keymaster

    @pereise1 very cool! Yeah etifoxine isn’t supposed to be very sedating but I was curious to see if that was true or if it might improve sleep. Tons of people with N seem to have comorbid anxiety so it might be a good choice for those folks over something more sedating like a benzo. I figured you’d be interested in it since it seems to help with the neural inflammation and repair.

    Interesting about that prostaglandin antagonist. It makes sense. From my understanding adenosine and prostaglandin increase during sleep deprivation and those increases may subsequently be responsible for the deep recovery sleep from prolonged sleep deprivation. I weirdly feel the most refreshed during recovery sleep from sleep deprivation – it’s the only time I can sleep without waking 3 or 4 times during the night. I actually wish there was a way to recreate that recovery sleep phenomenon without the actual sleep deprivation. But now your theory is sort of making me question whether prostaglandin is responsible for the recovery sleep or not. I haven’t had time to dig deep into the topic of prostaglandin but I’m very interested in it. Please keep up the fascinating research. And if you happen to know the mechanism behind recovery sleep, please do share!

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