Index General Discussion The Science of N Orexin research on the rise — stay strong!

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  • #6885
    PurpleyPurpley
    Participant

    I’ve said for a while that narcolepsy isn’t like other rare diseases, in that researchers have a keen interest in orexin neurons because medications for insomnia are BIG business. A better treatment for narcolepsy won’t be a blockbuster drug, so that alone doesn’t garner much interest. It could indeed be quite profitable thanks to the strategy of simply charging stratospheric prices which insurance companies will pay, like Jazz does with Xyrem, but it will never compete with the profits from a sleep medication like Ambien. But no matter what the reason, when you have lots of researchers looking at orexin, a better treatment for narcolepsy may be found along the way.

    Fortunately, orexin neurons are increasingly becoming a target of interest for researchers in both drug addiction and obesity. As an example, here’s an article about a recent study on binge-eating and orexin: Orexin Neurons are Promising Target for Medications to Treat Binge Eating

    Now, it’s true that most researchers looking for blockbuster drugs are looking for orexin blockers (antagonists), which are the opposite of what narcoleptics need; we need orexin agonists or medications that either boost orexin release or slow down reuptake or degradation after release. However, an important part of these types of research, when done by folks who truly have an interest in obesity and drug addiction rather than just an interest in finding a blockbuster drug, is learning about what factors trigger orexin release, or might even ramp up the production of orexin.

    So, this kind of stuff is what keeps me optimistic that much better treatments will be found in the next 10 years. After all, diabetes was universally fatal a generation ago, and now diabetics have so many medication options it’s hard to keep track of all of them. Parkinson’s disease affects many fewer people than diabetes and is a closer analogue to narcolepsy in that it’s also caused by the loss or dysfunction of neurons (producing dopamine), rather than cells in the pancreas (producing insulin.) Progress in developing treatments has been slower there. However, dopaminergic neurons are located in multiple locations of the brain. Any treatments that boost dopamine to a level needed to treat the slowed movements of Parkinson’s disease also boost levels of dopamine activity elsewhere in the brain, including areas that don’t need the boost. So you get unwanted side effects, like psychosis, caused by excessive dopamine in areas of the brain that don’t need it. Orexin neurons are at least limited to a specific location and set of functions. So, while an orexin agonist would undoubtedly have unwanted side effects if taken in excess, theoretically, if given in just the right amount, the person will simply be “normal” (in regard to sleep/appetite/etc.) just like a diabetic who receives the correct amount of insulin.

    OK, enough rambling. Hope this makes someone’s day, because it’s easy to get discouraged some days with the limited options right now — keep the faith!!

    "Even a soul submerged in sleep is hard at work and helps make something of the world."
    ― Heraclitus, Fragments
    #6904
    JasonJason
    Keymaster

    @purpley Thank you for taking the time to post this! Japanese researchers have already found orexin agonists that were effective in rodent models of narcolepsy. The Japanese seem to be at the forefront of narcolepsy research for whatever reason.

    It’ll be interesting to see what effect an orexin agonist would have on N2 since only 30% or so of diagnosed cases of N2 supposedly have low orexin. But for N1, an effective agonist, might essentially be the perfect treatment. I do wonder if an agonist would fix the disturbed sleep at night, however.

    Belsomra, the orexin blocker for insomnia was a huge bomb I believe.

    Also interesting is the recent findings regarding opiates and orexin and chronic opiates seemingly restoring orexin neurons. It’ll be interesting to see if that leads to new treatments.

    #6907
    FerretFerret
    Moderator

    @purpley and @jasonm
    Unless an orexin agonist is going to regenerate Orexin Neurons, I don’t think this is going to help anyone who’s had N1 with cataplexy for a while. I’d love to be wrong but acting on something that no longer exists is a pipe dream for me. Opinions?

    #6912
    JasonJason
    Keymaster

    @ferret While an orexin agonist wouldn’t cure the condition permanently, it would be effectively like insulin in type 1 diabetes. Insulin still works even though type 1 diabetics cannot produce insulin. The orexin neurons, which are toast in narcolepsy don’t alter how an agonist would work in this regard. The orexin agonists bind to the receptor sites (different than the neurons destroyed in N) for orexin, which are all over the brain and are still intact in narcolepsy. It’s the lack of activation of the receptors that causes symptoms. There’s just nothing to activate the orexin receptors in narcolepsy because ordinarily that’s what orexin would do.

    So basically an orexin agonist would bind to the receptors thus eliminating the majority of symptoms in narcolepsy no matter if you’ve had it for one year or fifty. It’d still require taking a pill everyday but it would beat the hell out of every other treatment currently available. Theoretically, it’d make a PWN feel just like they did before having N, at least during the day. It’ll probably be a decade or more before one gets approved though.

    Another example is like Belsomra, which is an orexin antagonist. It doesn’t reduce the amount of orexin in the brain or turn the orexin neurons off. It just prevents the naturally occurring orexin from binding to the orexin receptors. If a normal person took enough Belsomra, they’d get to experience what narcolepsy is like for a day or two until it wore off. Check out the side effects of Belsomra.

    #6915
    FerretFerret
    Moderator

    @jasonm Ah well, 10 years away eh? So, if I take it when I’m 77, I’ll feel like I did when I was diagnosed at 35? SIGN ME UP RIGHT NOW! ;)I’ll even do the trials for you.
    Thank you for the explanation. Couldn’t wrap my head around it…

    #6919
    PurpleyPurpley
    Participant

    @ferret – Right, @jasonm hit the nail on the head. An orexin agonist is exactly what most type 1 Ns would need, to replace the orexin that they’re no longer making. Some type 1 N’s might be able to get by with other types of medications, if they’re still making some orexin, but just not enough of it. For example, they could take a medication which would block the enzymes which break down orexin, thus keeping the orexin they have active for a longer time. That’s how some medications for dementia work — they block the enzymes which break down acetylcholine in the brain, which is a neurotransmitter which is needed for good cognitive functioning, so that the person’s acetylcholine hangs around longer.

    Now, since most type 2 N have normal levels of orexin, at least some of those folks probably have orexin resistance — the neurons which are supposed to respond when orexin binds to them just aren’t responding the way they should. Then the $64,000 question becomes whether or not it’s possible to overcome this resistence simply by boosting the levels of orexin or orexin agonists to a high enough point. If not, the medications which work for type 1 N won’t do a darn thing for them. And lord knows there are a dozen other possible theories of what particular quirk in brain functioning creates a type 2 narcoleptic or idiopathic hypersomniac, some of which would respond to orexin agonists or boosters, and others of which wouldn’t.

    I think the chances are excellent that type 1 Ns will have simple and effective treatment long before type 2 Ns, because all you need is that agonist and everyone with type 1 N is good to go. If you have type 1 diabetes, you just need insulin, period, and it works for everyone. My guess is that type 2 Ns are going to require a variety of treatments because we’re going to find a variety of underlying medical problems which can cause type 2 N. So while we’re still living in a world without treatments for either type 1 or type 2, I’m glad I’m type 2 N because I don’t have cataplexy. But five years from now the tables may have turned, and I may still be really sleepy while all you type 1’s out there are doing great! C’est la vie.

    "Even a soul submerged in sleep is hard at work and helps make something of the world."
    ― Heraclitus, Fragments
    #6926
    JasonJason
    Keymaster

    @ferret haha, okay well it won’t be a time machine! Pharmacology and neuroscience are incredibly complicated. I’m just grateful orexin seems to be simple compared to say the serotonin system. That one is so complicated, I gave up trying to understand it. Here’s a study on an orexin agonist in a mouse model. Note the agonist only worked in mice with destruction of the orexin neurons and not in genetically modified mice that had no orexin receptors.

    @purpley supposedly you can have N2 and then up to decades later develop cataplexy, at least according to my sleep doctor… I read some research suggesting in some patients with N2, despite having normal CSF orexin, showed pretty substantial cell death in the orexin producing neurons.

    #6935
    AvatarSleepy RBD
    Participant

    Great discussion, guys…Thanks for sharing your posts, links, etc.! It will be interesting to see how all of this plays out.

    @ferret Although we may not be able to reap the benefits of such, maybe there will be hope for the next generation. In the meantime, if you hear of those trials…well, let me know. I am willing to travel. : )
    @jasonm After reading the side effects of Belsomra, I think that I must have been taking it for years. I’m only kidding, of course, it just sounded a lot like the problems that I already have. Thanks for your insights and perspectives…
    In reference to cataplexy, in hindsight, I think that I had a subtle / milder to moderate form of cataplexy for a lot longer than I realized. If it had not increased in severity, I might have never recognized it for what it is. Through @sk8aplexy and ferret (along with others from the NN forums) sharing their knowledge and experiences, I was able to gain a much deeper understanding, recognition, and acceptance of it all. It can be very subtle, but also a beast.
    @purpley Thanks…moving forward, stronger and more knowledgeable together… : )

    #6941
    AvatarSleepy RBD
    Participant

    I came across this recently and thought that you guys might be interested, if you had not already seen it.
    Primary progressive narcolepsy type 1: The other side of the coin

    Have a fabulous Friday!

    #6946
    JasonJason
    Keymaster

    @sleepy-rbd Ahh great find on that study! I hadn’t seen it. I found this study because it cited the one you posted. Temporal Changes in the Cerebrospinal Fluid Level of Hypocretin-1 and Histamine in Narcolepsy

    Those studies make me wonder if some variants of N are more of a gradual neurodegenerative disease, more similar to Parkinson’s than purely an autoimmune disorder. That or if there are relapses of the autoimmune attack as in relapsing remitting MS, which is also believed to be autoimmune.

    Belsomra has awful patient reviews. Whoever thought blocking orexin was a great idea for insomnia should have talked to some PWN first, haha. I can’t believe it’s a controlled medication. Apparently inducing mild N is rewarding? The FDA has some brilliant logic.

    #6950
    AvatarSleepy RBD
    Participant

    @jasonm
    Interesting study…Thank you for the weekend reading material. haha
    I’m going to continue to follow some of the links and references from that study and see where they lead. It’s predicted to be a rainy day here with some storms moving through the area. With a little luck, maybe we will continue to maintain electricity and internet access.

    Edit: These links are not directly related to the subject at hand, but to the complexity of unlocking the mysteries of genetics, disease development, treatment, etc….
    Scientists solve longstanding biological mystery of DNA organization

    CRISPR-based tool maps gene function in human cells
    “Up until now science has produced a lot of data about specific mutations that drive human diseases, and we have a pretty good idea about which cells express what genes across human body, but we fundamentally don’t understand how genes work together in human cells,” Gilbert said. “With this new approach we are starting to build a portrait of how genetic interactions keep tissues healthy or to drive disease processes, but there is a whole lot more to learn.”

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