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

[Nick47]

RNID is funding a project at King's College London and the University of Nottingham to test if it is possible to lessen or even silence tinnitus, by blocking the activity of an ion channel associated with chronic pain.

Professor Peter McNaughton's team, based at King's College London, has identified that a type of ion channel, called HCN2, is responsible for driving neuropathic pain. Ion channels are proteins that span the surface membrane of electrically-active cells like nerve cells and allow charged particles (such as sodium or potassium ions) to pass in and out of cells – without these channels, ions cannot move across the cell's surface.

Professor McNaughton's team have shown that when ions flow through the HCN2 channels, they trigger the activation of pain-sensitive nerve fibres, creating a constant sensation of pain. When the researchers blocked these ion channels in mice, they were able to eliminate pain in a mouse model of chronic pain (Emery, E et al (2011) Science).

HCN2 channels are also found in the nerve fibres of the auditory system, which carry information from the ear to the brain. These fibres are often damaged after exposure to loud noise, which can lead to tinnitus. Some preliminary studies carried out by the King's College London team have shown that blocking HCN2 channels with selective drugs significantly reduces tinnitus in animal models.

The researchers now want to study the role of HCN2 channels in tinnitus in more detail. Professor McNaughton's team, working with experts in tinnitus at the University of Nottingham, will test the effectiveness of different drugs that block HCN2 channels in reducing tinnitus in animals. This work is being supported by one of our Translational Research Grants.

→ RNID: Chronic pain – how it might help us find a treatment for tinnitus
→ Academic profile of Prof. McNaughton
→ Publications by Prof. McNaughton

 

[KoolKat]

Very good find bro, I love hearing stuff like this I just hope it doesn't take a decade for human trials.

And wasn't this experiment done before?

 

[Nick47]

And wasn't this experiment done before?

@KoolKat, this research started about 3 years ago. It's in animal stage as far as I'm aware.

 

[Cbush]

Just wondering, is there anything new on this?

 

[Nick47]

Just wondering, is there anything new on this?

"Professor McNaughton's team, working with experts in tinnitus at the University of Nottingham, will test the effectiveness of different drugs that block HCN2 channels in reducing tinnitus in animals. This work is being supported by one of our Translational Research Grants."​

Looks like pre-clinical stage. There are a couple of papers published by him this year on pain and migraine but no human studies.

 

[HopeForSilence]

I got an answer from Professor McNaughton:

"Thank you for contacting me. Our work has shown that tinnitus is driven by the HCN2 isoform (protein conformation) – but unfortunately the HCN4 isoform is critical for a normal heart rate. What we need is to develop a drug that can distinguish between these two closely related forms of the protein. Will this be possible? It's not yet clear, and so a practical drug that can be used in the clinic is some distance away.

Sorry not to be able to be more optimistic. [...]"​

 

[KoolKat]

I got an answer from Professor McNaughton:

"Thank you for contacting me. Our work has shown that tinnitus is driven by the HCN2 isoform (protein conformation) – but unfortunately the HCN4 isoform is critical for a normal heart rate. What we need is to develop a drug that can distinguish between these two closely related forms of the protein. Will this be possible? It's not yet clear, and so a practical drug that can be used in the clinic is some distance away.

Sorry not to be able to be more optimistic. [...]"​

So is he confirming HCN2 Isoform is responsible for all this madness?

Or, because there have been no human clinical trials, this, like all the rest, is just a theory...

 

[Stayinghopeful]

I got an answer from Professor McNaughton:

"Thank you for contacting me. Our work has shown that tinnitus is driven by the HCN2 isoform (protein conformation) – but unfortunately the HCN4 isoform is critical for a normal heart rate. What we need is to develop a drug that can distinguish between these two closely related forms of the protein. Will this be possible? It's not yet clear, and so a practical drug that can be used in the clinic is some distance away.

Sorry not to be able to be more optimistic. [...]"​

Sorry, but can someone explain if this is related to potassium channels and if this all ties into the Dr. Susan Shore's theory?

 

[AnthonyMcDonald]

Sorry, but can someone explain if this is related to potassium channels and if this all ties into the Dr. Susan Shore's theory?

There isn't much relation of KCNQ2/KCNQ3 potassium channels to Dr. Shore, other than her briefly going over that information in her papers, and both potential treatments being related to the Dorsal Cochlear Nucleus.

 

[Stayinghopeful]

There isn't much relation of KCNQ2/KCNQ3 potassium channels to Dr. Shore, other than her briefly going over that information in her papers, and both potential treatments being related to the Dorsal Cochlear Nucleus.

So basically this is good news as there is now a prominent hypothesis/theory that's finally agreed upon as a potential treatment if I'm looking at it in a positive light?

 

[AnthonyMcDonald]

So basically this is good news as there is now a prominent hypothesis/theory that's finally agreed upon as a potential treatment if I'm looking at it in a positive light?

You can't say that they are exactly the same. The Susan Shore device has a very large impact on stimulating the somatic systems, so to speak (trigeminal nerve, etc), not only the DCN. I can't say they are exactly the same. But certainly Susan's profound success is a positive indicator for this potential potassium channel treatment.

 

[dd314]

RNID is funding a project at King's College London and the University of Nottingham to test if it is possible to lessen or even silence tinnitus, by blocking the activity of an ion channel associated with chronic pain.

→ RNID: Chronic pain – how it might help us find a treatment for tinnitus
→ Academic profile of Prof. McNaughton
→ Publications by Prof. McNaughton

After some research into this, there's already a drug that blocks this particular channel, called Ivabradine. It's used for POTS which I and many other people have after getting COVID-19. There is one single anecdote of it stopping someone's tinnitus:

"Yes, it definitely has. These are the improvements that I have noticed:

• NO FAINTING EPISODES!
• No more tinnitus
• No more tremors
• Drastically reduced dizziness and brain fog
• Reduced fatigue
• Reduced blurry vision and hearing/visual disturbances
• Reduced breathlessness and palpitations
• Reduced nausea
• Better memory and concentration
• Dramatically reduced exercise and heat intolerance
• Less problems with reduced sweating
• Fewer issues with cold extremities and blood pooling
• Fewer low moods (I would not say I felt depressed but I did find myself feeling overwhelmed and down at times)
• Better sleep and fewer nightmares"

Source: https://liveyourselfbetter.wordpres...-beta-blockers-ivabradine-and-a-happy-ending/

 

[AnthonyMcDonald]

After some research into this, there's already a drug that blocks this particular channel, called Ivabradine. It's used for POTS which I and many other people have after getting COVID-19. There is one single anecdote of it stopping someone's tinnitus:

"Yes, it definitely has. These are the improvements that I have noticed:

• NO FAINTING EPISODES!
• No more tinnitus
• No more tremors
• Drastically reduced dizziness and brain fog
• Reduced fatigue
• Reduced blurry vision and hearing/visual disturbances
• Reduced breathlessness and palpitations
• Reduced nausea
• Better memory and concentration
• Dramatically reduced exercise and heat intolerance
• Less problems with reduced sweating
• Fewer issues with cold extremities and blood pooling
• Fewer low moods (I would not say I felt depressed but I did find myself feeling overwhelmed and down at times)
• Better sleep and fewer nightmares"

While this does show promise, further research needs to be conducted. One thing that makes someone better can make another worse.

 

[Tomas80]

I'm going to try Ivabradine. Off label. Fingers crossed, I'm going to be a guinea pig. I will try anything, I can't describe the suffering. I will keep you updated...

 

[Nick47]

I'm going to try Ivabradine. Off label. Fingers crossed, I'm going to be a guinea pig. I will try anything, I can't describe the suffering. I will keep you updated...

@Tomas80, sorry. I understand.

Did you try Latuda?

 

[Tomas80]

@Tomas80, sorry. I understand.

Did you try Latuda?

I got Ivabradine first. I'll try itfor a few weeks. I won't try Latuda, but when I finish Ivabradine, I will then try Reagila (Cariprazine).

 

[chinup]

After some research into this, there's already a drug that blocks this particular channel, called Ivabradine. It's used for POTS which I and many other people have after getting COVID-19. There is one single anecdote of it stopping someone's tinnitus:

"Yes, it definitely has. These are the improvements that I have noticed:

• NO FAINTING EPISODES!
• No more tinnitus
• No more tremors
• Drastically reduced dizziness and brain fog
• Reduced fatigue
• Reduced blurry vision and hearing/visual disturbances
• Reduced breathlessness and palpitations
• Reduced nausea
• Better memory and concentration
• Dramatically reduced exercise and heat intolerance
• Less problems with reduced sweating
• Fewer issues with cold extremities and blood pooling
• Fewer low moods (I would not say I felt depressed but I did find myself feeling overwhelmed and down at times)
• Better sleep and fewer nightmares"

I am diagnosed with POTS and have had it for several years, even before COVID-19. I'd absolutely try this medication if there's a chance it could (safely) reduce my tinnitus. I'll start researching it.

To be clear: Ivabradine blocks both HCN2 and HCN4? I'm not a biologist and don't really understand how these channels work...

 

[Nick47]

@chinup, HCN4 is to do with the heart. I think it slows it down. As you know, as soon as you stand up, you get tachycardia if you have POTS.

I saw this on Twitter:

"My tinnitus improved, not necessarily because of, but whilst taking, Ivabradine. My BP is low all the time. I had to stop taking all meds & supplements for a few days recently, & the tinnitus was back full-time, so *something* is making a difference to me."​

 

[IndyMLVC]

Did you try Latuda?

Does Latuda do it as well? My psych had suggested that.

 

[Nick47]

@IndyMLVC, does Latuda do what? What are you asking?

 

[Tomas80]

Third day Ivabradine 5 mg daily. I just took my heart rate - 49.

OMG. I'm normally in the 70s to 90s due to stress and anxiety from the tinnitus. No change in tinnitus yet.

 

[IndyMLVC]

@IndyMLVC, does Latuda do what? What are you asking?

I'm asking what does Latuda do? Why was it brought up?

 

[Nick47]

I'm asking what does Latuda do? Why was it brought up?

@IndyMLVC, it was brought up by 1 member who had significant success. It has a pharmacological profile that suggests it 'might' work for others too, based on antagonism of 5-HT receptors and dopamine agonists. Read the medication thread.

It's also relatively new to market.

 

[dd314]

I am diagnosed with POTS and have had it for several years, even before COVID-19. I'd absolutely try this medication if there's a chance it could (safely) reduce my tinnitus. I'll start researching it.

To be clear: Ivabradine blocks both HCN2 and HCN4? I'm not a biologist and don't really understand how these channels work...

I think Ivabradine is nonselective; it blocks all HCN's.

 

[Tomas80]

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 :/

 

[dd314]

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 :/

I mean, I was just speculating, I don't think jumping on heart meds is smart. If you're really that desperate, Flexeril and Valium are two drugs that actually do give temporary relief, especially if you have somatic tinnitus.

 

[Nick47]

Prof. McNaughton gave a recent interview to an online audiologist. He summarised tinnitus to chronic neuropathic pain, saying that tinnitus is peripheral in origin.

He was successfully able to eliminate behavioral evidence of tinnitus using a HCN2 blocker. The tinnitus suppression was temporary.

In theory this may equate to humans taking a drug twice a day to suppress tinnitus over a 24 hour period.

A little bit more:

HCN2: a key ion channel driving pain, migraine and tinnitus

We would all like to avoid pain – but acute pain (the pain felt shortly after injury) is essential for life, because it is a critical warning system that protects us from damage. Chronic pain, by contrast, is a long-lasting pain that often serves no useful purpose.

What causes pain? No-one doubts that acute pain is caused by activation of ion channels in sensory neurons by noxious stimuli. The discovery of TRP channels activated by heat and Piezo channels activated by mechanical stimuli won the Nobel prize recently. These ion channels, when opened by a painful stimulus, generate an inward current that triggers firing of action potentials in sensory nerve fibres. Transmission to appropriate centres in the brain activates the conscious sensation of pain.

When it comes to chronic pain, opinion is much more divided. Which channel might provide the inward current necessary to trigger nerve activity? My own group recently made a novel proposal. HCN (Hyperpolarization-activated, Cyclic Nucleotide gated) ion channels are activated by inflammatory mediators that elevate the intracellular level of cAMP and so generate an inward current that can initiate action potential generation in pain-sensing nerve terminals. We proved this idea by showing that genetically deleting the HCN2 isoform (one of four in total) in pain-sensing nerves abolished the neuropathic pain caused by nerve injury (see refs below). Similar results were obtained with a drug that blocks HCN ion channels. Importantly, there was no effect on acute pain thresholds. These results show that the HCN2 ion channel is a key driver of chronic pain.

In more recent work we have extended the idea that HCN2 may drive abnormal excitability of sensory neurons to other pathologies – painful diabetic neuropathy, arthritis, migraine and even to tinnitus (ringing in the ears caused by loud noise), with promising results in all these apparently distinct conditions.

We conclude that HCN2 is a critical target for the development of novel analgesics. A challenge, however, has been to develop selective blockers that will inhibit HCN2 ion channels without interfering with the closely-related HCN4 ion channels that are important in regulating the heart.

My money is still on a pill being the first effective treatment for tinnitus.

You may be correct. I got in touch with Prof. Peter McNaughton regarding the HCN2 drug target that he is involved in developing. He also commented on the work of the Shore Lab.

Dear Nick,

Thank you for your email and also for the interesting series of websites. As I think I mentioned in the interview, I am not really a tinnitus person (my main work is on pain) but I work with the group of Alan Palmer in Nottingham who has an extensive track record in hearing. Alan and others in the group are in touch with the interesting work in the Susan Shore group.

The cochlear nucleus is the first stop for signals originating in the auditory nerve. The increased activity that the Shore group have identified in cochlear neurons lines up nicely with our views that in fact abnormal activity originates in the auditory nerve itself. The auditory nerve is a more promising place to look for pharmacological targets because it is in the peripheral nervous system – targets in the CNS almost inevitably involve psychotropic effects which may be very undesirable. We are trying to develop peripherally restricted drugs which will not have CNS effects. The main problem is that the HCN2 (nerve) and HCN4 (heart) are closely similar and getting selectivity between them has not proven to be easy.

The Xenon and Biohaven people are interested in CNS targets (epilepsy, major CNS disorders) and so they need their drugs to be CNS penetrant.

With very best wishes,
Peter Mcnaughton

 

[Olly132]

@Nick47, very interesting.

I wonder if this could also be a treatment for noxacusis?

 

[Nick47]

I wonder if this could also be a treatment for noxacusis?

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.

 

[KoolKat]

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.

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

This looks to have crazy potential, I just hope it doesn't take them 20 years to get a move on. If Dr. Shore's device works, then I'm sure this is going to do something.