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

[BB23]

Prof. McNaughton is not a tinnitus expert.

Thank God for that, otherwise he'd be pushing down something akin TRT down our throats instead of actually finding out the true cause of it.

 

[BB23]

I decided to read Prof. Tzounopoulos' paper explaining the relationship between the HCN and KCNQ channels in depth and post it here again in case it gets overlooked.

The problem is that this paper only mentions the prevention of tinnitus BEFORE IT DEVELOPS, and it doesn't even mention the term acute ONCE. It doesn't say anything about chronic. That's why the term "resilience" is used. Even in his YouTube interview (46.30), he used the term "prevent," not cure or eliminate. He mentions the drug will help with "central tinnitus" (yay, if true), but I don't see the research on it. More information can be found in it other than the parts I have quoted here.

Also, give the Major Issues section a read if you decide to look at the paper.

Considering all the information, I'm inclined to agree with @Nick47's point. It's crucial to ask ourselves: could these drugs potentially offer a breakthrough in the treatment of chronic/central tinnitus?

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

To distinguish between these two possibilities, we measured HCN channel activity 4 days after noise exposure. Our results revealed that although noise-exposed mice showed significantly reduced KCNQ2/3 currents in fusiform cells 4 days after noise exposure (Figure 3B), HCN channel activity was not different between sham-exposed and noise-exposed mice (Figure 6A,B). These results indicate that the decrease in KCNQ2/3 activity happens before the reduction of HCN channel activity.

Taken together, our results suggest that increases in KCNQ2/3 channel activity promote a decrease in fusiform cell HCN channel activity and resilience to tinnitus.

Pharmacological enhancement of KCNQ channels with retigabine reduces spontaneous firing rate in fusiform cells (Figure 7—figure supplement 1C,D) and promotes a decrease in HCN current amplitude (Figure 6D). Therefore, we propose that decreases in spontaneous firing that may be caused by the enhancement in KCNQ2/3 channel activity lead to changes in intracellular calcium, which, in turn, may trigger a homeostatic mechanism that decreases HCN currents in an effort to normalize spontaneous spike rates. Immunohistochemical studies have shown that the HCN2 subunit is expressed in fusiform cells that lack HCN1 subunit expression (Koch et al., 2004), suggesting that HCN2 isoforms may mediate the noise-induced plasticity in fusiform cells. Therefore, we propose that manipulations that reduce HCN2 channel activity may serve as potential therapeutic path for preventing the development of tinnitus.

we show that noise exposure leads to down regulation of KCNQ2/3 channel activity by 4 days after noise exposure. At this time, no tinnitus has developed yet, probably due to the absence of fusiform cell hyperactivity. Mice that show a natural recovery of KCNQ2/3 channel activity and a reduction in HCN channel activity display normal level of spontaneous firing rates and are resilient to tinnitus. Mice that show preservation of reduced KCNQ2/3 channel activity until 7 days post noise exposure show fusiform cell hyperactivity and develop tinnitus

 

[Nick47]

I don't have much faith in the Kv7.2/3 channel openers anymore. Far too many loose conclusions are drawn just because Retigabine was effective for 50% of patients. Retigabine acts on all sorts of receptors at the same time. Studies on Kv7.2/3 demonstrate prevention, not treatment. We interviewed Professor Peter McNaughton yesterday. Let's wait for his research in HCN2 molecules.

 

[BB23]

We interviewed Professor Peter McNaughton yesterday. Let's wait for his research in HCN2 molecules.

My only worry:

This drug doesn't cross the blood-brain barrier, correct?

My tinnitus wasn't noise-induced. Mine is neurological, with visual snow syndrome. I don't know if the source of my tinnitus stems from the inner ear.

So, in case this form of tinnitus originates in the brain, not the inner ear, if that's a thing, can a drug like this help out?

The pessimist (realist) in me says no.

Anyway, I can't wait for the interview. I hope he'll give us the answers we are looking for.

 

[Nick47]

This drug doesn't cross the blood-brain barrier, correct?

Correct, it does not penetrate into the brain.

 

[Utdmad89]

My only worry:

This drug doesn't cross the blood-brain barrier, correct?

My tinnitus wasn't noise-induced. Mine is neurological, with visual snow syndrome. I don't know if the source of my tinnitus stems from the inner ear.

So, in case this form of tinnitus originates in the brain, not the inner ear, if that's a thing, can a drug like this help out?

The pessimist (realist) in me says no.

Anyway, I can't wait for the interview. I hope he'll give us the answers we are looking for.

Doesn't all tinnitus technically originate from the brain?

 

[StoneInFocus]

Update:

We are interviewing Prof. McNaughton this coming Tuesday. We already have an episode lined up for publishing in May (arguably one of our most exciting ones to date), but Prof. McNaughton's episode will come right after that.

Please submit your questions below!

It's far too late now, but I would be curious to know where he got the idea from
that tinnitus originates from type II afferents in the inner ear.

It could explain why intratympanic Lidocaine injections work for tinnitus.

If only there were a way to knock or block these type II afferents out forever without affecting type I afferents.

 

[StoneInFocus]

Any updates?

 

[Nick47]

Any updates?

I think the podcast was recorded two months ago. I would think formatting it is time-consuming, though! I have heard nothing in general from the RNID about his work since November 2023. Personally, I think this avenue holds some promise, though.

 

[cjbhab]

I don't know if the source of my tinnitus stems from the inner ear.

I wonder if anybody's tinnitus stems from the inner ear. I'm inclined to say no. My friends somehow have perfect hair cells even though they went to all the same concerts and events I did. I don't buy it. Something else is at play.

 

[Utdmad89]

I wonder if anybody's tinnitus stems from the inner ear. I'm inclined to say no. My friends somehow have perfect hair cells even though they went to all the same concerts and events I did. I don't buy it. Something else is at play.

You have no way of knowing this.

 

[Nick47]

My friends somehow have perfect hair cells even though they went to all the same concerts and events I did. I don't buy it. Something else is at play.

This research suggests that tinnitus is peripheral, with the abnormal activity starting in the peripheral nerve cells in the spiral ganglion due to their polarization. Animal data show we can change the polarization by blocking the HCN2 channels, thereby reducing tinnitus. Other papers show the involvement of these channels.

What we desperately need is human data to refute or support this hypothesis.

The brain is undoubtedly involved, as we know it is. The question is where the firing or signal starts. Why does bypassing these damaged fibers (cochlear implants) often reduce tinnitus, even when the patient is in a soundproof booth? This suggests it's not the sound masking effect itself.

 

[Utdmad89]

I think the podcast was recorded two months ago. I would think formatting it is time-consuming, though! I have heard nothing in general from the RNID about his work since November 2023. Personally, I think this avenue holds some promise, though.

I think this avenue could also be extremely important for noxacusis.

 

[Nick47]

I think this avenue could also be extremely important for noxacusis.

Yes as it was originally being developed for chronic neuropathic pain.

 

[Ferna]

How long would it take to turn this into a viable treatment? The website did say that they are working with a drug company.

 

[Nick47]

How long would it take to turn this into a viable treatment? The website did say that they are working with a drug company.

They are working with Merck. We are waiting for the publication of the Tinnitus Talk Podcast, which was recorded in May of this year. Basically, it worked in animals with noise-induced tinnitus but had side effects. They had some new molecules to try in November 2023; however, I do not know where they are now.

The RNID has extended its funding.

 

[Utdmad89]

How long would it take to turn this into a viable treatment? The website did say that they are working with a drug company.

Probably at least a decade.

 

[StoneInFocus]

How long would it take to turn this into a viable treatment? The website did say that they are working with a drug company.

Probably at least a decade.

I don't know if Prof. McNaughton is still investigating type II afferents in relation to tinnitus or if he is just focused on finding a compound, but I think the former is a more promising avenue.

In theory, there are multiple ways to silence type II SG afferents. If Prof. McNaughton manages to find convincing evidence that type II afferents are indeed the culprit in tinnitus, it could open to door to more researchers investigating this area and possible ways to silence these neurons.

@Nick47, do you know if the answers Prof. McNaughton gives here are new or from around November? It says the page was updated on 4 March.

it says that:

"There are two main achievements that we hope for:

• A better understanding of what drives tinnitus. If our hypothesis that HCN2 ion channels (a type of protein in some nerve cells, including auditory nerve cells, that are involved in sending signals to the brain) are critical in tinnitus is correct, then this will be a major advance.
• Development of drugs called HCN2 ion channel blockers (drugs that prevent HCN2 ion channels from signalling to the brain) as treatments for tinnitus. We are collaborating with the drug company Merck with the aim of developing these drugs into treatments for both neuropathic pain (a type of chronic pain where there is no detectable underlying cause in the body) and for tinnitus."

 

[Nick47]

@Nick47, do you know if the answers Prof. McNaughton gives here are new or from around November? It says the page was updated on 4 March.

I know no more than you. I await the Tinnitus Talk Podcast to be uploaded. Only the interviewer will know more than me, and maybe there was no new information at the time of the interview in May 2024. In November 2023, the RNID told me on Twitter that the team at Kings College London had identified some additional promising compounds. The original compounds that worked in animals were cardiotoxic. Therefore, the search was on for more selective compounds that would not also target the HCN4 proteins, which are numerous in the cardiac muscle.

 

[Hazel]

I know no more than you. I await the Tinnitus Talk Podcast to be uploaded. Only the interviewer will know more than me, and maybe there was no new information at the time of the interview in May 2024. In November 2023, the RNID told me on Twitter that the team at Kings College London had identified some additional promising compounds. The original compounds that worked in animals were cardiotoxic. Therefore, the search was on for more selective compounds that would not also target the HCN4 proteins, which are numerous in the cardiac muscle.

Hey! We've been too busy with other projects like a website overhaul and an exciting new research project that we'll be announcing next week. Next to day jobs and family obligations, there just hasn't been time for editing, audio cleaning, transcribing, subtitling, writing blurbs, and all the other tasks that come with publishing a podcast -- there's still dozens of hours of (volunteer) work that needs to go into this, and unfortunately it's not at the top of our priority list right now, but we're doing our best...

When I spoke to Prof. McNaughton, his research seemed to be have been stalled due to lack of funding for some time, so I don't think much has changed/moved in the past few months. Prof. McNaughton believes he may be able to solve the selectivity issue, but he needs new funding to move forward.

 

[Utdmad89]

When I spoke to Prof. McNaughton, his research seemed to be have been stalled due to lack of funding for some time, so I don't think much has changed/moved in the past few months. Prof. McNaughton believes he may be able to solve the selectivity issue, but he needs new funding to move forward.

Great. Nothing is coming to save those with noxacusis.

 

[gotearsimhere]

Great. Nothing is coming to save those with noxacusis.

I want to add a little hope for the noxacusis people.

I know this thread is about HCN2, but HCN1 is also significant in neuropathic pain. It's not as well proven as HCN2 for noxacusis/tinnitus.

A company that has a selective HCN1 blocker is already in the preclinical stage.

This shows selective targeting of HCN isoforms is possible.

→ Akelos

 

[StoneInFocus]

I want to add a little hope for the noxacusis people.

I know this thread is about HCN2, but HCN1 is also significant in neuropathic pain. It's not as well proven as HCN2 for noxacusis/tinnitus.

A company that has a selective HCN1 blocker is already in the preclinical stage.

This shows selective targeting of HCN isoforms is possible.

→ Akelos

HCN2 channels are more heavily expressed on type II SGNs than HCN1 channels, see this.

 

[Utdmad89]

HCN2 channels are more heavily expressed on type II SGNs than HCN1 channels, see this.

The optimism didn't last long.

 

[BB23]

It will still be ten years away, ten years from now.

 

[gotearsimhere]

HCN2 channels are more heavily expressed on type II SGNs than HCN1 channels, see this.

Dang.

 

[Utdmad89]

It will still be ten years away, ten years from now.

Better than never at all.

 

[BB23]

Better than never at all.

It won't mean much to me after I'm gone. We can only last so long as a species, you know.

 

[Nick47]

We've been too busy with other projects

I understand how busy you've been now!

 

[Nick47]

Here's an update by RNID. I had speculated the research had ran out of money. It's a bit ambiguous. However, I like that they engage with people. Sod those that do not!