P2Y12 Antagonists (Clopidogrel, Ticlopidine, Ticagrelor) for Noxacusis?

P2Y12 receptor blockers are a group of antiplatelet drugs. This group of drugs includes: clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor. An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. After noise exposure, purinergic signaling is up-regulated in the cochlea. P2Y receptors become more active, affecting potassium channels and contributing to noxacusis:

Unmyelinated type II afferent neurons report cochlear damage

So in this study, the excitability of type 2 afferents, which share many similarities to c fiber nociceptors, which warn of tissue damage, was measured after application of a P2Y agonist, which was increased by it. If I understood it correctly, ATP activates P2Y receptors which in turn close the KNCQ channels. After noise damage ATP concentrations increase, which causes P2Y receptors to become more easily agonized, which in turn leads to a greater effect on the potassium channels.

So theoretically, an P2Y4-6 antagonist prevents ATP binding to its receptors and thereby reduce closure of the potassium channels. However, the only drugs currently available that antagonize P2Y receptors act on P2Y12 specifically, and the paper makes no mention of that particular receptor. But these P2Y12 antagonists, such as clopidogrel, cangrelor and ticlopidine, might help with noxacusis as well. In this paper, 6 different P2Y12 antagonists were tested in mice models of acute (nociceptive), inflammatory and neuropathic pain, and it was found that they had alleviating effects in all three domains. This paper elucidates the mechanism of P2Y12 mediated pain:

The paper cites some more evidence for P2Y12 antagonists in the treatment of pain:

So, what do you think about this? Will P2Y12 blockers help in the treatment of noxacusis? If so, to what extent? How long would we need to use it? Which particular P2Y12 will be the best for our purpose? After what period of usage will we notice effect? Will the possible side effects of these drugs be worth the risk?

I would love to hear your opinions.

 

@StoneInFocus, amazing find and theory. I'm wondering if the potential side effects from it being ototoxic even matter? Since the medication prevents the closure of the potassium channels, and should prevent worsening tinnitus and hyperacusis.

Do we know if any drug is being developed for a P2Y4-6 antagonist?

I'm also wondering how this fits in with Megan Beers Wood's study on CGRP blockers and their effect on noxacusis?

 

Where does it say the medication causes cell death in the cochlea?

 

I could only find evidence for aspirin being ototoxic, not the other P2Y12 blockers.

To be honest I am not really sure. I made this thread specifically for the P2Y12 receptor because it is the only one for which antagonists are readily available for us to try.

Gefapixant, a P2X3 antagonist developed by Merck, has been investigated in two Phase 3 clinical trials for the treatment of chronic cough. It is currently available in Japan under the brand name Lyfnua, and is awaiting approval for the US and EU markets. I will make a thread about it soon.

So the study of Paul Fuchs et al. investigates the excitability of type 2 afferents in mice cochlear after the application of various substances. The focus of that study is the nerve fibers themselves. The research area of Megan Beers Wood is much less specific. It is my understanding that Wood and her team are currently developing a mice model for pain hyperacusis. Wood wants to investigate the relationship between inflammation, which, if I understood it correctly, is signified by increased immune cell concentrations, in the cochlear as a whole and painful sensitivity to sound in mice. As stated in the article above, "activation of P2Y12 receptor can regulate immune cell activity, release inflammatory factors, and damage neurons." According to this article, "P2Y12 is functionally expressed not only in platelets and the microglia but also in other cells of the immune system, such as in monocytes, dendritic cells, and T lymphocytes... Several studies were carried out, showing that blocking P2Y12 can be beneficial for the outcome of various inflammatory conditions, such as sepsis, asthma , rheumatoid arthritis and neuroinflammation." So it seems like very real possibility that P2Y12 antagonists reduce inflammation in the cochlear.

Here's the thing though. Wood discovered that CGRP-a signal blocking actually INCREASED the number of immune cells in the cochlear after noise exposure. So if inflammation contributes to pain hyperacusis, CGRP-a blockers could very well WORSEN our condition.

 

Sorry, I think I misread that! Do we know what kind of side effects the medication could have?

 

I'd advise you to look up the side effects of the available P2Y12 antagonists yourself, see if they are acceptable to you or not. You could also consult your doctor.

 

I definitely will!

This is all so confusing lol, but it's very informative! I'm wondering if something like Rimegepant actually helped people with noxacusis or not, and specifically if it helps inner ear noxacusis.

Do you think we could bring this up to a researcher currently studying inner ear noxacusis? I would love to see something being developed for this type of approach, as this theory definitely holds some merit in my opinion!

I'm also wondering if we'll get that study released from Wood soon? I really want to see what they've found so far and if it could actually harm us more than help.

 

Looks like she is the guest of honour at an upcoming tinnitus & hyperacusis conference. Hopefully she provides an update on her research.

Management of the Tinnitus and Hyperacusis Patient: 30th Annual Conference

 

I’m hoping that her being the guest of honour means thst she’ll have something interesting to share in regards to her research but maybe that’s just misplaced optimism.

 

Snap; I was really holding out hope for CGRP-blockers. Beer's research does seem to be in line with other findings though:

Inflammatory complications of CGRP monoclonal antibodies: a case series

So it seems that in some cases CGRP-blocking helps reduce inflammation & pain, while in others it does the opposite? This is very odd. I know I've read about at least one person finding relief from pain hyperacusis with a CGRP-blocking migraine med (Tegretol). Oh, the mysteries of the human body...

On another note, forgive my lack of research, but what is the relationship between P2Y12 & CGRP?

 

I wonder what kind of noxacusis and pain they had? I wonder if we can narrow down if migraine meds will work for someone based on their specific pain symptoms.

 

Are you sure Tegretol is a CGRP blocker? I couldn't find any information that would support that. Isn't it more likely that any pain hyperacusis relief from that drug is due to its voltage-gated sodium and/or calcium channel blocking properties?

Yeah we went a bit off topic here, but the only relationship between P2Y12 and CGRP that I am aware of is that they are both implicated in inflammation in some ways. But like you mentioned, CGRP can have both pro-inflammatory and anti-inflammatory effects.

It's best we leave discussion about CGRP to another thread.

 

I think it's important to realize that, as far as I know, only the P2Y2 receptor is shown (2010) to be expressed specifically on type II afferent SGNs in adult rat cochlea. In regards to the P2Y12 receptors, they were "confined to the mesenchymal cells of Reissner's membrane at a low expression level and the perinuclear region of spiral ganglion neurons at a moderate expression."

In this study about the "Design, synthesis and biological evaluation of suramin-derived dual antagonists of the proinflammatory G protein-coupled receptors P2Y2 and GPR17", it is stated that
"Only few antagonists of P2Y2R antagonists are available so far. AR-C118925 is one of the most potent and selective antagonists described to date and represents a tool compound, but is not suitable as a therapeutic drug probably due to its insufficient pharmacokinetic properties. Suramin is non-selective antagonist of P2Y receptors, and inhibits the P2Y2R with moderate potency (IC50 according to literature ca. 50 μM). Its high molecular weight (1429 g/mol) and multiple negatively charged sulfonate groups prevent its peroral bioavailability as well as brain penetration" (meaning it might not cross the BLB to reach the cochlea).

According to Wikipedia, "Suramin is not orally bioavailable and must be given intravenously. Intramuscular and subcutaneous administration could result in local tissue inflammation or necrosis."

This review article (2023) discusses the role of P2Y2 receptors in various diseases. "There are currently three patents for the use of the P2Y2R antagonist AR-C118925 as a therapeutic intervention in human disease. The patents describe the use of P2Y2R antagonism to prevent diet-induced obesity, IBD , and tumor metastasis by blocking neutrophil migration to the tumor microenvironment and/or sites of metastases."

I couldn't find any information about AR-C118925 being tested on humans yet. As for the other receptors in the P2Y family, I have not checked yet.

 

Sorry, my error! Tegretol is absolutely not a CGRP blocker, it only blocks pain in the manner you describe. I was thinking of a different med, which I can't remember now - but I will mention when I find the information again.

Okay, so here's something that may be interesting. You mentioned that Aspirin is a P2Y(12) blocker. This got me thinking about willow bark (known as nature's Aspirin) & in turn about foods that are high in salicylates (which also have blood-thinning properties). One of these foods is ginger, which seems to relieve burning pain for a number of people with pain hyperacusis.

You also mentioned that P2Y12 is implicated in inflammation... & foods high in salicylates are known as being anti-inflammatory.

So could it be that we can achieve significant P2Y blocking through diet? And could the willow bark supplement potentially help as well?

The concern here would of course be possibly inducing ototoxicity through too large of a consumption of salicylates...

Also, I wonder, if Megan Beers Wood's research followed the research on the type II afferents, why did she focus on CGRP-blocking rather than P2Y blocking? I really think there may be a relationship here that would be interesting to find out.

Where did you find evidence that Aspirin is a P2Y12 blocker? It seems it may be in a class of its own as far as blood thinners are concerned? If so, my theory falls apart :/

Cheers,
Maddy

 

Hey, no worries.

In the paper mentioned above it is said that Aspirin blocks P2Y12, however I could not find any information about that elsewhere, so I take that information with a grain of salt.

You know, for the past few weeks I've been reading lots of papers and articles trying to understand how noxacusis in particular works and what could possibly treat or cure it. I've come to understand that multiple factors are involved with the increased sound-sensitivity and sensitization of type II afferent spiral ganglion neurons. Some of the possible factors identified by Paul Fuchs (and Megan Wood!) are purinergic upsignalling in the cochlea, meaning P2Y and P2X receptors become more easily activated, increased ribbon number and size on outer hair cells, and cochlear inflammation. Recently a team of researchers has identified the HCN2 ion channel, which is expressed on type II SGNs, as possibly being implicated in tinnitus and hyperacusis. Researchers have also found that the histamine receptors are found in the inner ear of mammals (people report improvements on a low histamine diet). All of this is only touching the very surface of the ion channels, receptors, immune cells and other mechanism involved with increased type II spiral ganglion sensitivity. And then we haven't even started on the role of other regions of the body in noxacusis, such as the middle ear or the central nervous system. So in other words, it is a super complex puzzle to figure out what we as sufferers can do to alleviate our symptoms. Until some sort of miracle therapy comes about, a treatment of noxacusis will consist of a combination of drugs, supplements, and lifestyle modifications, instead of each of these interventions separately. A single diet, drug or supplement will in all likelihood only provide little or only temporary relief.

So unless we want to wait god knows how long until a drug is delivered to us on a silver platter, which may never even come, we as a community need a different battle approach if we want to get rid of our hyperacusis and noxacusis in particular. So if we want to try to treat our condition ourselves, what I think we need to do is as follows:

1+2. Gain a deeper understanding of biological and pharmacological principles. Think about concepts such as ion channels, membrane potentials, receptors, bio-availability, different tissues, blood labyrinth barrier, peripheral versus central sensitization, inflammation etc.

1+2. Start reading scientific articles about our condition to gain a deeper understanding of our illness. Following the latest conferences on hearing disorders.

3. Use our gathered knowledge as a framework to understand more deeply the symptoms of our own and others, and how reported symptom improvements, such as after certain drug use or lifestyle modifications, came about because of these factors. So for instance: Ambroxol has helped people with burning pain but not stabbing pain + Ambroxol is a sodium channel blocker ---> Are burning and stabbing pain caused by two different mechanisms? + How are sodium channels involved with acute stabbing pain? + Will other sodium channel blockers help with burning pain as well? Etc.

4. Figure out the most important ion channels, receptors or other mechanisms involved with noxacusis.

5+6. Find out which compounds in which combinations will be helpful in treating these components of noxacusis. Reading articles and contacting doctors or researchers to ask their advice. Are they able to cross the blood labyrinth barrier? Could they be ototoxic? Are they safe to take? Are the adverse effects worth the benefits? Which compounds are the most optimal for long term use?

5+6. Find out the practicality of taking these compounds, and which one is the best to take. Are they expensive? Where to find the cheapest source? Are they currently being developed, and is there a possibility for early access? What about possible interactions? What are the available administration routes?

7. Acquiring the compounds. This can be done in coordination with each other. If some of the compounds are available through a prescription, each of us can try out a different one to compare effects. If the compounds are available as a supplement or chemical, we can try to buy it in bulk and distribute it among ourselves as to cut costs.

8. Testing the compound combinations out. Keeping careful notes of our symptom severity and possible side effects, and sharing our experiences with each other.

9. Adjusting doses and specific compound combinations, maybe consulting doctors.

10. Repeating the steps until we have found a working combination of compounds, maybe curing our tinnitus in the process.

I know it sounds like a lot of work, but we got to escape from this hell at all costs. The sense of gratefulness and joyfulness we will experience will be worth it.

 

Should we contact Megan Wood or another researcher involved in inner ear noxacusis and ask if they are looking into researching P2Y4-6 and P2Y12 antagonists, as well as P2Y2 receptors?

 

I too have been doing a fair bit of relevant reading (most recently about peripheral & central sensitization) & have come to many of the same conclusions as you. I need to take a break from research & lengthier posting but will come back in the near future to say more

 

I don't see how that is going to solve anything for us at the moment.

I have attached the results of a study in which 40 flavonoids were tested for their ability to agonize the P2Y2 receptor.

 

Thank you for linking the study. I'm sorry, I'm a little confused, how wouldn't that be beneficial? If they were able to create a P2Y4-6 antagonist, wouldn't that solve our inner ear noxacusis? Since ATP seems like the thing that triggers the domino effect?

 

As I've said, our noxacusis is multifactorial. Just antagonizing one receptor is not going to solve our condition. The Paul Fuchs paper never explicitly said that the P2Y4-6 receptors are implicated in noxacusis. If there are not antagonists out there already available that target these receptors, it's utterly pointless to send an email. Besides that, Megan Wood is aware of these receptors and their possible role in hyperacusis. It is already super hard to just alleviate noxacusis pain symptoms on their own. That is only something morphine is reliably able to do.

I don't think there is going to become a drug available in AT LEAST the next five years that will help significantly with noxacusis on its own, whether that is a potassium or purinergic antagonist or whatever, and not completely render us unconscious or threaten our safety.

If we want something to alleviate our symptoms, we are going to need some type of multimodal therapy.

If we are really lucky we can find some sort of drug or supplement combo that will help us enough to have somewhat normal lives. But that is not even guaranteed. For me, waiting god knows how many years until researchers have cooked up some drug for us to use is not going to be an option.

I don't use this forum for some sort of psychological reasons. I do not visit this website to get some sort of gratifying feeling because of a vague hope of a cure. My only purpose here is to find something to treat our hyperacusis as fast as possible.

 

Great find (though I think you mean antagonize?)! Might try to source me a tangerine peel supplement (looks like there are powders?).

Ginger has Quercetin, so I wonder whether that's why it works? I wonder whether a Quercetin supplement would do the same?

My only concern is that Ginkgo biloba flavonoids (including quercetin & kaempferol) have demonstrated significant ototoxicity in zebrafish. I wonder whether this is because of P2Y2 receptor antagonism (haven't read the full article yet)? If so, that might be concerning for other flavonoids & P2Y2 antagonism as a whole...

Maddy

 

My mistake, yes I meant antagonize, good catch.

The problem is that we know at which concentrations in vitro the compounds interact with the P2Y2 receptor on a cellular level, and we somehow got to translate that to a human dosage we have to take in order for the compound to reach the inner ear and have the same effect on the P2Y2 receptors. Multiple pharmacokinetical factors like bioavailability, half-life and the ability to cross the BLB are involved with this question.

That is a good find. The article suggests that these flavonoids cause hair cell death by inducing the production of reactive oxygen species (cellular stress response). I don't think P2Y2 antagonism has anything to do with it.

Maybe there are some flavanoids or other natural compounds that antagonise the P2Y2 receptor and are not ototoxic?

The article also suggests co-administration with an antioxidant to prevent flavonoid induced ototoxicity.

 

I just came across this article, which demonstrated that N-acetylcysteine protected uraemic patients with CAPD peritonitis from drug-induced ototoxicity.

It seems like NAC supplementation might be a good idea if we are going to experiment with supplements and/or medication.

 

Recommended tool compounds and drugs for blocking P2X and P2Y receptors

I am not really sure but I think the authors mean that regular Ambroxol doses are sufficient to antagonize the P2X2 receptor to some extent.

I wonder what the share of P2X2 versus sodium channel blockage is in treating burning hyperacusis pain, if it helps at all with it.

If one P2Y blocker can already help with burning pain, imagine what multiple, in combination with other drugs, can do.

 

Yeah, I've been thinking about this as well... how drugs, supplements, etc. influence the body in many ways & so it's hard to tell which mechanism is causing the alleviation of a certain symptom (e.g., burning pain). And it could be the influence of more than one mechanism as well (e.g., as you describe with ginger).

 

Regarding that research paper you posted the other day on herbal potassium channel openers, were you able to find anything that was listed that wasn't ototoxic? Ginger doesn't act on the potassium channels we need, and Quercetin can be ototoxic. Maybe fitweed or cilantro?

 

Quercetin was shown in vitro to induce moderate hair cell damage at a concentration of 50 μM in vitro.



The P2Y2 IC50 value for Quercetin was 41 μM.

I'm still not ready to exclude all flavonoids yet, but Quercetin seems pretty risky to take, even though I am not entirely sure if these two concentrations can be compared with each other one to one.

Maybe there is some flavonoid that has greater affinity for the P2Y2 receptor and is less ototoxic?

In any case, co supplementation with an antioxidant seems like a must.

 

July 21, 2023:

Because Gefapixant cannot cross the BBB, it still remains to be seen whether it can treat noxacusis or not.

But it looks worthwhile to try out once it becomes more easily available. Maybe there are even people on here from Switzerland or Japan who can give it a shot.

The event is already tomorrow, I don't think anyone is attending. Maybe it's better to send her an email.

 

If you send her an email and hear back, definitely let us know what she says. I want to know if she spit some heat at this conference.

 

"Following a CHMP opinion [which for gefapixant was July 21] the European Commission takes usually its decision, a legally binding authorisation, after 67 days."

Here's a graph of the average time between marketing authorization and patient access for medicines in Europe as of 2023, by country.