Can Blocking HCN2 Ion Channels Silence Tinnitus? RNID Funds Prof. McNaughton's Team to Find Out

[Nick47]

Did they try this on humans yet, or are these animal findings?

Animals.

 

[ErikaS]

Yes, I think it's very plausible. As noxacusis is chronic for some, the alignment with chronic neuropathic (nerve) pain is strong. The fact it silences tinnitus in the animal studies is promising, although not all animal research translates to humans.

I would think noxacusis is also peripheral in generation if sound causes pain and therefore central gain/hyperacusis is no longer the cause.

They found evidence of the HCN2 protein in the spiral ganglion in the inner ear and they are sure that tinnitus elimination was not due to the drug's interaction on the brain as the drug is known to not be able to penetrate the blood brain barrier. In other words, the drug only acted on the peripheral nerves. These findings support a peripheral starting point of tinnitus generation that then alters the firing rate in the DCN.

So the issue going forward will be to raise significant funds to develop a more selective drug that does not interfere with HCN4. Big pharma would be ideal.

Big pharma should be notified as I believe they would be ALL over this. To have a drug dismantle conditions such as tinnitus and other pain areas that does not affect the central nervous system and carry the side effects that those drugs do, like holy shit. These findings and this proposed peripheral nerve intervention drug, in my opinion, should be the main focus moving forward as a medication for tinnitus management. Don't be so sensitive, HCN4! Lol.

As always, thank you @Nick47 for keeping us going with the most up to date research and communication.

 

[Nick47]

There will be a presentation on this work at the TRI 2023 conference.

My friend and colleague, Mark Wallace, will be presenting our @RNID sponsored work that he is leading, looking into the role of HCN2 channels in tinnitus and as a drug treatment target, at the Tinnitus Research Initiative 2023.

 

[Aussie Lea]

Big pharma should be notified as I believe they would be ALL over this. To have a drug dismantle conditions such as tinnitus and other pain areas that does not affect the central nervous system and carry the side effects that those drugs do, like holy shit. These findings and this proposed peripheral nerve intervention drug, in my opinion, should be the main focus moving forward as a medication for tinnitus management. Don't be so sensitive, HCN4! Lol.

Maybe the lack of objective marker makes the big pharma less inclined to be involved? I'm sure they know about this development.

Even with the full backing of big pharma this would be 8-10 years away at best... I wish I could be put into cryogenic sleep until we have something!

 

[ErikaS]

Maybe the lack of objective marker makes the big pharma less inclined to be involved? I'm sure they know about this development.

Even with the full backing of big pharma this would be 8-10 years away at best... I wish I could be put into cryogenic sleep until we have something!

Oh my gosh, I say this ALL the time! Our community would benefit SO much from cryogenic sleep. Mentally, emotionally, and physically. Then just wake us up when something is available, and who the hell knows maybe our tinnitus, reactivity, hyperacusis, etc. would possibly be more mild upon awakening due to letting the brain actually rest and heal? The dream upsides compared to being awake with this condition with nothing in our hands yet to use/take make me wish it existed.

 

[Hazel]

There will be a presentation on this work at the TRI 2023 conference.

I just checked and it seems to be a poster, not a presentation. It's a bit of a challenge, as I'm already having to choose between attending different parallel presentations, while networking and trying to record footage, so the posters become a bit of an afterthought (and there are so many of them!). But I will try to seek this one out tomorrow and take a picture of it if I can

 

[Hazel]

Update: see attached the poster. I found out I have access to at least some of the posters through the conference app (not everyone seems to have uploaded their poster though). I'm not 100% sure we're allowed to share; researchers can be sensitive about that if it concerns unpublished data, so may have to take it down later, but here you go

By the way, I haven't spotted the presenter and not sure what we he looks like but will keep an eye out...

 

[Nick47]

I have spoken to Peter McNaughton and he says we are fine to share @Hazel. He offered to email it to me the other day. I agreed, however couldn't open it on my phone. There are no secrets from their side as the research is publicly funded.

 

[EDDTEKK]

Did they test acute or chronic tinnitus?

 

[Hazel]

It's an animal study, meaning they induce tinnitus in animals, so by definition it's acute, which is one of many limitations of animal studies. Your question will become relevant if they ever reach the stage of human clinical trials, but most drug candidates either never reach that stage or turn out not to translate well from animal to human models.

 

[ma7555]

I read about Ivabradine, seems like it's a very serious medication that controls the heart pacemaker current. I do not suggest anybody to try it. It needs medical supervision due to the risk of atrial fibrillation.

Also, it seems that this paper in 2015 mentions that HCN2 along with KCNQ channels are the ones responsible for tinnitus:

Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus

 

[Nick47]

My first concerns is, not only are they animal studies, but mice. Although the University of Nottingham study was done on Guinea pigs, which have auditory systems similar to humans. My other concern is the differentiation between ACUTE vs. CHRONIC tinnitus.

 

[StoneInFocus]

Update: see attached the poster. I found out I have access to at least some of the posters through the conference app (not everyone seems to have uploaded their poster though). I'm not 100% sure we're allowed to share; researchers can be sensitive about that if it concerns unpublished data, so may have to take it down later, but here you go

By the way, I haven't spotted the presenter and not sure what we he looks like but will keep an eye out...

View attachment 55068

Interesting, this is the first time that I've read about the type 2 afferents being involved in tinnitus. I suppose that if that connection receives greater attention within the pharmaceutical/scientific community, it would significantly speed up the development of a drug or therapy that would help treating noxacusis. It's also quite auspicious that such a long-standing and big company as Merck is working on a HCN2 blocker (for chronic pain) instead of just some questionable start-up firm. The combined potential market for tinnitus and chronic pain would be enormous, especially in light of the opioid epidemic in America. The only bad news is that this 'Merck 2' drug is still in the preclinical phase.

They found evidence of the HCN2 protein in the inner ear and they are sure that tinnitus elimination was not due to the drug's interaction on the brain as the drug is known to not be able to penetrate the blood brain barrier. In other words, the drug only acted on the peripheral nerves. These findings support a peripheral starting point of tinnitus generation that then alters the firing rate in the DCN.

I looked at the poster but nothing was mentioned about administration route. In a previous study by McNaughton et al. they injected Ivabradine intraperitoneally. Now I am not an otolaryngologist but according to this study, "the [blood labyrinth barrier] is thought to have similarities to the blood-brain barrier (BBB)". Therefore, unless a drug is applied directly to the cochlea, it must have similar properties to BBB crossing drugs to pass the BLB, isn't it? Without inferring it from the results of the Nottingham study, how could they really be sure the drug reached the auditory nerve, and how would that even work? Maybe the HCN2 blockers alleviated tinnitus through some other mechanism than silencing the type 2 afferent SGNs?

The smallest dose of Ivabradine is 5 mg. Even though I only took half of that, I still had pain in my heart. I had to stop taking it. I'm not going to risk my heart. The experiment did not bring success :/

First of all I salute you for trying something out.

The Ivabradine dosage used in the Nottingham study on mice was 5 mg/kg. According to this calculator, which admittedly uses a very roughly estimated conversion rate, that equates to 0.407 mg/kg for humans, which would mean 28.5 mg if you were to weigh 70 kg. So a dosage of 2.5 mg might be far from enough to have any effect on one's tinnitus. If we want to draw any conclusions about its effectiveness in treating tinnitus we'd probably have to use the maximum dosage of 15 mg. The lady from the blog already experienced tinnitus relief at a 5 mg dosage, but we have to keep in mind that her tinnitus seemed to co-occur with heart issues.

I've read online that chest pain is a known side effect of Ivabradine. Your pain might not necessarily be an omen of a heart attack or a sign of some sort of heart dysfunction or damage. Did your doctor prescribe you this medication? During my first cannabidiol trial I also experienced pain around the liver area, but a blood test revealed that my liver was functioning totally normal. I am not saying your symptoms in particular were due to some placebo effect, but for anyone interested in trying Ivabradine, the possibility of those kind of effects happening is important to keep in mind.

Ivabradine is generally considered a safe drug. It was already approved in Europe in 2005. "A [2016] literature review of the major published studies that assessed the efficacy and safety of ivabradine was performed. Most of the reviewed studies concluded that ivabradine exerted beneficial effects with a tolerable safety profile. Specifically, a favorable benefit-risk profile was found when ivabradine was used for patients with an HR ≥70 beats per minute. Reports revealed that the most common ADR was bradycardia, which was expected. Other safety risks or ADRs were comparable to other prescribed drugs." Another study found that "Ivabradine was effective and well-tolerated in CHF patients seen in clinical practice throughout 1 year of treatment. Adverse drug reactions were noted in 26 patients (3%), and were in line with the known safety profile of ivabradine. Ivabradine has also been studied for neuropathic pain in patients with normal heart function. Maybe I'm missing something here but if Ivabradine in normal doses, let alone half of the smallest dose, causes serious heart issues we would probably know it by now, wouldn't we?

Besides that, there are protocols in place for safe usage of Ivabradine. According to this leaflet from EMA, "if, during treatment, heart rate decreases below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward including the lowest dose of 2.5 mg twice daily. After dose reduction, heart rate should be monitored. Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist despite dose reduction."

Now I am not necessarily recommending anyone here to take it for their tinnitus or hyperacusis, but I think it's important that we do not discourage sufferers from trying Ivabradine on the basis of an exaggerated idea of its unsafety. It would be a shame if tinnitus sufferers would too scared to try it even though they could very well benefit from it without suffering from any serious adverse effects, wouldn't it? As long as people consult with their doctor, keep track of their heart rate and occuring side effects and discontinue taking the drug when the situation warrants it, from what I've read online Ivabradine poses zero risk for any serious heart issues. That is just my humble opinion.

 

[Nick47]

I looked at the poster but nothing was mentioned about administration route. In a previous study by McNaughton et al. they injected Ivabradine intraperitoneally. Now I am not an otolaryngologist but according to this study, "the [blood labyrinth barrier] is thought to have similarities to the blood-brain barrier (BBB)". Therefore, unless a drug is applied directly to the cochlea, it must have similar properties to BBB crossing drugs to pass the BLB, isn't it? Without inferring it from the results of the Nottingham study, how could they really be sure the drug reached the auditory nerve, and how would that even work? Maybe the HCN2 blockers alleviated tinnitus through some other mechanism than silencing the type 2 afferent SGNs?

Having had communication with Professor McNaughton, I can answer some of your questions, but first of all, a little bit about him.

His specialty is neuropathic pain and he specialises in pharmacology. He has held a hypothesis for some time that tinnitus is a peripheral phenomenon, usually triggered after insult to the cochlear nerves. He is not a tinnitus researcher per say.

He identified a protein called HCN2 that was involved in chronic neuropathic pain and checked to see if it was present in the inner ear. It was.

He then teamed up with a research team that studies hearing at Nottingham University, led by Alan Palmer, to test this hypothesis.

His hypothesis was tested on Guinea Pigs and using the startle test, they concluded that the HCN2 blocker eliminated the tinnitus, whilst the medication was in the system.

They have not moved to human trials as the medication is not selective enough and has affinity for the HCN4 protein involved in heart function.

With regards to it being able to cross the BBB, it cannot. The route of administration does not affect this as the molecules are to large to cross the BBB and get filtered out. It is easy to take a sample of brain tissue and check. The medication did not and cannot get into the brain.

I'm not 100% on the hypothesis but I'm very interested as there is some evidence to support it.

 

[StoneInFocus]

the molecules are to large to cross the BBB and get filtered out.

Yes precisely. If the molecules of the drug are too big to pass through the BBB, how are they going to pass through the BLB, which supposedly has similar permeability, and reach the auditory nerve unless the drug is applied locally, e.g., intratympanically?

 

[Nick47]

the drug are too big to pass through the BBB, how are they going to pass through the BLB, which supposedly has similar permeability, and reach the auditory nerve unless the drug is applied locally, e.g., intratympanically?

I don't know about the BLB. It's a good question, and one I'm sure he would be happy to answer. Drop him an email. He responded to me within hours.

 

[Josh59]

@Nick47, when you talk about peripheral nerves, could this also affect the trigeminal nerve, which innervates the tensor tympani muscle? This muscle causes pain when it contracts or vibrates during sound input.

Another question for everyone:

With regard to the HCN2 ion channel and potassium channels (e.g., KCNQ2/3), what can be done to ensure that these are studied in several countries? For example, in the European Union with their UNITI project? How can we make our health organisations more aware of this research, so as to create more synergy between these researchers and clinicians and, above all, more financial investment?

 

[StoneInFocus]

Here is my email exchange with Prof. McNaughton, omitting the usual formalities:

It is my understanding that the blood-labyrinth barrier has similar permeability as the BBB.

So my question is, if Ivabradine cannot cross the BBB, how can it cross the BLB to reach the auditory nerve, or did you administrate the drug locally to the inner ear?

Ivabradine does suppress tinnitus in animal models, and as you say this drug does not penetrate the blood-brain barrier. We were interested in why it acted on afferent nerve fibres of the auditory nerve. We found experimentally that, contrary to what others in the field have thought, the drug does penetrate the auditory nerve, which therefore lies outside the blood-brain barrier. In this respect it is the same as most other sensory nerves, e.g. those of the somatosensory system that lie outside the BBB (including their nerve cell bodies). Thus I am unsure whether it penetrates the BLB, but for sure it reaches the auditory nerve.

I am not very knowledgeable of the anatomy of the inner ear, and I previously thought that the auditory nerve was protected by the BLB, but from your answer I gather that the auditory nerve is not encapsulated by that barrier, is that correct?

I am interested to know how you found out that Ivabradine reaches the auditory nerve when administrated systematically.

Did you infer it from the startle responses?

If so, how would you exclude other factors like a lowered blood pressure having an impact on tinnitus perception?

Are you also certain that Ivabradine prevents the depolarization of type II afferents specifically?

We showed that the auditory nerve was accessible to ivabradine by direct measurement of ivabradine concentrations in auditory nerve dissected out of ivabradine-injected guinea pigs. Concentrations in the nerve were similar to those in blood and very significantly above brain levels.

About the type II afferents, we suspect that they are the targets of ivabradine and that block of HCN2 ion channels prevents firing in these axons. However we lack direct evidence for this hypothesis. What is certain is that several structurally distinct HCN2 blockers all suppress tinnitus, as measured in the Gap Prepulse Inhibition of Acoustic Startle (GPIAS) test.

 

[Nick47]

Here is my email exchange with Prof. McNaughton, omitting the usual formalities:

Well done for asking. Professor McNaughton is a very good man and I hope you thanked him. His expertise is pharmacology and he has held lecturing posts at Cambridge University, one of the best in the world.

The question we need answering is will this translate from Guinea Pigs to Humans? It did in the Shore Lab.

If it does, then developing a selective HCN2 blocker becomes the aim.

 

[ErikaS]

Here is my email exchange with Prof. McNaughton, omitting the usual formalities:

Great questions, @StoneInFocus. I really hope they can figure out how to not affect HCN4. If that can be done with a pharmaceutical that does not cross the BBB and central nervous system, it could move through trials pretty quickly.

 

[StoneInFocus]

Great questions, @StoneInFocus.If that can be done with a pharmaceutical that does not cross the BBB and central nervous system, it could move through trials pretty quickly.

I'm not really sure if 'quickly' is the right word here. To be honest I'm not holding my breath for specific HCN2 blockers becoming available any time soon. Merck 2 is still in the preclinical phase so that might take at least a decade, let alone that other compound.

I'm personally most interested in to what extent the HCN2 channel is implicated in noxacusis. Now that I know that Ivabradine can reach the auditory nerve through systematic administration, it has definitely become a more probable option on my table as of now. I think the supposed dangers of Ivabradine seem to be overestimated here as it has been tested on healthy subjects with a normal heart rate as well. But of course bradycardia will limit its effective usage for some people, like the guy in this thread.

 

[ImmortalWombat]

All these researchers should join Tinnitus Talk.

 

[Nick47]

They updated me today. They have identified several promising molecules since June this year.

 

[StoneInFocus]

They updated me today. They have identified several promising molecules since June this year.

Promising in what way exactly? Have they said anything else? Do you know what their plans are for now?

All these researchers should join Tinnitus Talk.

I think we would need an entirely new category here if we'd want that to be fruitful. Maybe you could call it 'Discussion' or something. There's so much emotion involved in every thread, even in those in the Research News subsection. I don't think researchers and doctors are in the mood to shift through that constantly. Reading about people being depressed and such is not something you would want to do after clocking out as a doctor or researcher. Important information and conclusions become lost in textual currents of hope and despair.

Besides that, they would probably constantly get bombarded with questions and complaints, partly because people are unwilling to do even the slightest bit of reading.

Things like people sending hate mail to researchers like Susan Shore and Thanos Tzonoupolous is probably not helping either, and in all likelihood further damages the reputation of tinnitus and hyperacusis sufferers as nothing but hypochondriacs and crazy people.

 

[Nick47]

Promising in what way exactly? Have they said anything else? Do you know what their plans are for now?

The response I got from RNID:

The researchers have identified additional promising compounds since June. The project is still ongoing and we'll be sure to share the full results when they are available. Please do check our website for updates.

→ https://rnid.org.uk/hearing-research/

 

[StoneInFocus]

Inhibition of hyperpolarization-activated cyclic nucleotide-gated channels with natural flavonoid quercetin

Quercetin is a natural flavonoid which has been reported to be analgesic in different animal models of pain. However, the mechanism underlying the pain-relieving effects is still unclear. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in controlling pacemaker activity in cardiac and nervous systems, making the channel a new target for therapeutic exploration. In this study, we explored a series of flavonoids for their modulation on HCN channels. Among all tested flavonoids, quercetin was the most potent inhibitor for HCN channels with an IC50 value of 27.32 ± 1.19 μM for HCN2. Furthermore, quercetin prominently left shifted the voltage-dependent activation curves of HCN channels and decelerated deactivation process. The results presented herein firstly characterize quercetin as a novel and potent inhibitor for HCN channels, which represents a novel structure for future drug design of HCN channel inhibitors.

If anyone has access to the article and could post it here, I would greatly appreciate it.

The key question is whether Quercetin taken in the standard oral dosage (500-1000 mg per day) is enough to reach sufficient concentrations in the blood to antagonize the HCN2 channel to a symptom relieving extent.

According to the poster, the HCN2 channel is also expressed in the "auditory brain", so for that fact alone the tinnitus-alleviating effect of Quercetin could potentially be greater than that of Ivabradine as Quercetin crosses the BBB.

We know that the main mechanism by which Ivabradine reduces heart rate is by blocking the HCN4 channel. Unfortunately, I have not read the article so I do not know whether the potency of Quercetin in inhibiting HCN2 is similar to that of inhibiting HCN4. But if it is, and the standard Quercetin dose is sufficient to block HCN2 channels (which we hope), you would expect symptoms of bradycardia at regular Quercetin doses too, unless there is some sort compensatory mechanism at play.

 

[Nick47]

Big pharma should be notified as I believe they would be ALL over this. To have a drug dismantle conditions such as tinnitus and other pain areas that does not affect the central nervous system and carry the side effects that those drugs do, like holy shit.

Big pharma are involved. Merck to be exact, as they have a licensing agreement with Kings College London.

From the RNID website:

King's College London is collaborating with MSD (tradename of Merck & Co., Inc., Kenilworth, NJ, USA) for the development of compounds that inhibit HCN2 under an exclusive research agreement.

 

[annV]

Inhibition of hyperpolarization-activated cyclic nucleotide-gated channels with natural flavonoid quercetin

Quercetin is a natural flavonoid which has been reported to be analgesic in different animal models of pain. However, the mechanism underlying the pain-relieving effects is still unclear. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in controlling pacemaker activity in cardiac and nervous systems, making the channel a new target for therapeutic exploration. In this study, we explored a series of flavonoids for their modulation on HCN channels. Among all tested flavonoids, quercetin was the most potent inhibitor for HCN channels with an IC50 value of 27.32 ± 1.19 μM for HCN2. Furthermore, quercetin prominently left shifted the voltage-dependent activation curves of HCN channels and decelerated deactivation process. The results presented herein firstly characterize quercetin as a novel and potent inhibitor for HCN channels, which represents a novel structure for future drug design of HCN channel inhibitors.

If anyone has access to the article and could post it here, I would greatly appreciate it.

The key question is whether Quercetin taken in the standard oral dosage (500-1000 mg per day) is enough to reach sufficient concentrations in the blood to antagonize the HCN2 channel to a symptom relieving extent.

According to the poster, the HCN2 channel is also expressed in the "auditory brain", so for that fact alone the tinnitus-alleviating effect of Quercetin could potentially be greater than that of Ivabradine as Quercetin crosses the BBB.

We know that the main mechanism by which Ivabradine reduces heart rate is by blocking the HCN4 channel. Unfortunately, I have not read the article so I do not know whether the potency of Quercetin in inhibiting HCN2 is similar to that of inhibiting HCN4. But if it is, and the standard Quercetin dose is sufficient to block HCN2 channels (which we hope), you would expect symptoms of bradycardia at regular Quercetin doses too, unless there is some sort compensatory mechanism at play.

Here it is.

 

[Nick47]

Thanks again @annV.

The issue is what dosage would be possibly effective and safe? It has only weak affinity for HCN1 & HCN4.

If you are going to supplement, in terms of a company, I recommend Lamberts UK. It is the company that provided Alpha-Lipoic Acid for the tinnitus trial, as they make pharmaceutical grade supplements. I have no affiliation with them whatsoever.

→ Lamberts: Quercetin

 

[StoneInFocus]

It has only weak affinity for HCN1 & HCN4.

Where does the article say that or how did you come to the conclusion?

It reads: "Our results firstly showed quercetin was a potent inhibitor for HCN channels with preferential affinity on HCN2 compared to HCN1 or HCN4", and "quercetin also blocked HCN1 or HCN4 less potent compared to the effect on HCN2."

That fact alone doesn't necessary mean that Quercetin has 'weak' affinity for HCN1 and HCN4.