Noise-Induced Hearing Loss Alters KCC2 and GABA Inhibition in the Auditory Centers

[gameover]

I have not seen this new paper by Arnaud Noreña and others linked or discussed here yet (forgive if it is linked somewhere). It suggests the real culprit behind both tinnitus and hyperacusis is a decrease in KCC2. It does not say directly, but apparently, KCC2 levels in VCN can recover (some attribute VCN to be responsible for hyperacusis), while not so much in DCN.

Also, various things that were discussed as tinnitus remedies, like Oxytocin, Kampo medicine, and the Keto diet, supposedly help increase KCC2 levels.

→ Noise-Induced Hearing Loss Alters Potassium-Chloride CoTransporter KCC2 and GABA Inhibition in the auditory centers

 

[Nick47]

Nice find, @gameover. I remember reading one of Shore's/Mark's papers and they discussed the VCN as a part of the brain involved in hyperacusis.

 

[gameover]

Clarification regarding:

It does not say directly, but apparently, KCC2 levels in VCN can recover (some attribute VCN to be responsible for hyperacusis), while not so much in DCN.

Actually, the paper does say that. What I meant is that this perhaps may be the reason why hyperacusis can improve, while tinnitus rarely does - which the paper does not say, i.e.:

DCN -> tinnitus -> KCC2 does not recover, so tinnitus rarely improves.
VCN -> hyperacusis -> KCC2 may recover, so hyperacusis can improve.

Also, I was searching for other things that can increase KCC2 levels - allegedly, Resveratrol does do that.

 

[Note]

Interesting find! Unfortunately, results for the Ketogenic diet aren't that great.

 

[Utdmad89]

Clarification regarding:

Actually, the paper does say that. What I meant is that this perhaps may be the reason why hyperacusis can improve, while tinnitus rarely does - which the paper does not say, i.e.:

DCN -> tinnitus -> KCC2 does not recover, so tinnitus rarely improves.
VCN -> hyperacusis -> KCC2 may recover, so hyperacusis can improve.

Also, I was searching for other things that can increase KCC2 levels - allegedly, Resveratrol does do that.

What is Resveratrol?

 

[HighleyTall]

It seems I need to switch from white to red wine.

 

[Note]

I took NAD+ & Trans-Resveratrol for around 2 months. I didn't notice any effect.

 

[Nick47]

Bear in mind hardly any of the Resveratrol will survive the digestion process. Maybe 5-10%.

 

[BB23]

It has been shown that KCC2 is regulated by 5-hydroxytriptamine (5-HT) type 2A receptors to serotonin. This regulatory mechanism may account, at least in part, for the link between the serotoninergic system and tinnitus and/or hyperacusis

So I extrapolate taking antidepressants not only mess up HCN2 channels but KCC2 channels as well, huh... They are working on an NKCC1 drug named IAMA-6, but the paper says NKCC1 channels are unaffected. Nobody is working on a drug that restores the KCC2 channels.

Great.

I also believe the malfunction of the HCN2 and KCC2 channels creates a downstream effect that takes out the potassium channels, meaning unless we fix what was damaged upstream, potassium channel drugs won't cure us, and they will have to be taken forever.

 

[Jammer]

What is Resveratrol?

Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources of Resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries, and peanuts.

Resveratrol has antioxidant, anti-inflammatory, immunomodulatory, glucose and lipid regulatory, neuroprotective, and cardiovascular protective effects. Therefore, it can protect against diverse chronic diseases, such as cardiovascular diseases (CVDs), cancer, liver diseases, obesity, diabetes, Alzheimer's disease, and Parkinson's disease.

 

[gameover]

Bear in mind hardly any of the Resveratrol will survive the digestion process. Maybe 5-10%.

I guess so. I did not want to suggest that Resveratrol would be an effective therapy, but it should not hurt.

I've been doing more digging for papers on KCC2 enhancement and found the below. KCC2 is being looked at in the context of epilepsy, just like the potassium channel opener drugs are:

1. Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice
2. The Expanding Therapeutic Potential of Neuronal KCC2
3. Discovery of Small Molecule KCC2 Potentiators Which Attenuate In Vitro Seizure-Like Activity in Cultured Neurons
4. Potential therapeutic role of SIRT1 in age- related hearing loss

It does not look like we are anywhere close to a drug. This is sobering because if the paper linked in the opening comment of this thread is right and KCC2 is the culprit, we are far, far away from any pharmacological therapy.

 

[Josh59]

This is sobering because if the paper linked in the opening comment of this thread is right and KCC2 is the culprit, we are far, far away from any pharmacological therapy.

What are the reasons for this?

Is it challenging to work on?

 

[BB23]

Is it challenging to work on?

I heard they tried it in the past without success, but then I stumbled into this paper. They seemed to achieve it with gene editing tech, CRISPR.

There are two channels that regulate chloride: NKCC1 and KCC2. You'd require NKCC1 to go low and KCC2 to go high.

This is from Wikipedia:

KCC2 is a potassium (K+)/chloride (Cl−) symporter that maintains chloride homeostasis in neurons. The electrochemical chloride gradient established by KCC2 activity is crucial for classical postsynaptic inhibition through GABAA receptors and glycine receptors in the central nervous system.

In the case of neuroinflammation, NKCC1 goes high while KCC2 goes low. A model suggests that tinnitus is caused by neuroinflammation, so the info fits here, except for the NKCC1 bit.

As I have said, an NKCC1 drug is in the works. Still, the paper says these channels are unaffected, meaning the only thing we will be able to modify will be the potassium via potassium channel openers until they make a KCC2 drug. I also believe that, along with HCN2 channels, KCC2 is our main target in tinnitus. Fixing KCC2 will theoretically cure many forms of epilepsy as well. On visual snow forums, KCC2 has been suspected to be the cause for a long time...

 

[gameover]

I heard they tried it in the past without success, but then I stumbled into this paper. They seemed to achieve it with gene editing tech, CRISPR.

There are two channels that regulate chloride: NKCC1 and KCC2. You'd require NKCC1 to go low and KCC2 to go high.

This is from Wikipedia:

In the case of neuroinflammation, NKCC1 goes high while KCC2 goes low. A model suggests that tinnitus is caused by neuroinflammation, so the info fits here, except for the NKCC1 bit.

As I have said, an NKCC1 drug is in the works. Still, the paper says these channels are unaffected, meaning the only thing we will be able to modify will be the potassium via potassium channel openers until they make a KCC2 drug. I also believe that, along with HCN2 channels, KCC2 is our main target in tinnitus. Fixing KCC2 will theoretically cure many forms of epilepsy as well. On visual snow forums, KCC2 has been suspected to be the cause for a long time...

It is very interesting. Is it really the seminal discovery of the cause of tinnitus and the key to treating, maybe even curing it?

When you read about the down-regulation of KCC2, it seems it is behind so many diverse things, from epilepsy to genetic disorders like Rett Syndrome...

 

[Utdmad89]

I heard they tried it in the past without success, but then I stumbled into this paper. They seemed to achieve it with gene editing tech, CRISPR.

There are two channels that regulate chloride: NKCC1 and KCC2. You'd require NKCC1 to go low and KCC2 to go high.

This is from Wikipedia:


In the case of neuroinflammation, NKCC1 goes high while KCC2 goes low. A model suggests that tinnitus is caused by neuroinflammation, so the info fits here, except for the NKCC1 bit.

As I have said, an NKCC1 drug is in the works. Still, the paper says these channels are unaffected, meaning the only thing we will be able to modify will be the potassium via potassium channel openers until they make a KCC2 drug. I also believe that, along with HCN2 channels, KCC2 is our main target in tinnitus. Fixing KCC2 will theoretically cure many forms of epilepsy as well. On visual snow forums, KCC2 has been suspected to be the cause for a long time...

So, nobody is working on a KCC2 drug, even with the information available? Honestly, what the hell?

 

[gameover]

So, nobody is working on a KCC2 drug, even with the information available? Honestly, what the hell?

Kinda crazy. I would understand that a drug for tinnitus is not sexy, but for epilepsy or Rett Syndrome - very much so...

Hopefully something is happening, but this stuff seems fairly new. We are still in the Middle Ages when it comes to treating neurological conditions.

 

[Fields]

On visual snow forums, KCC2 has been suspected to be the cause for a long time...

I'm not on any visual snow syndrome forums, as I learned to live with it 19 years ago, but this is really interesting to read. It would be kind of nice if everything did not look like a grainy photo taken in high ISO anymore.

I've read about the possible connection between tinnitus and visual snow syndrome before, though. It would be neat if the same drug could alleviate or cure both afflictions.

 

[gameover]

This paper says there are two KCC2 enhancer drugs: PCPZ (Prochlorperazine) and CLP-257.

Prochlorperazine is an old drug. Per Wikipedia:

Prochlorperazine, formerly sold under the brand name Compazine among others, is a medication used to treat nausea, migraines, schizophrenia, psychosis and anxiety.

There is an an older thread about it on the forum.

This very recent paper mentions CLP257 and related CLP290. As far as I could tell, there have been no clinical studies on humans.

But it also mentions OV350, an epilepsy drug in Ovid Therapeutics' pipeline.

I also found AXN-006 by Axonis Therapeutics, targeting spinal injuries. They are working on a preclinical trial apparently.

 

[Nick47]

there are two KCC2 enhancer drugs: PCPZ (Prochlorperazine) and CLP-257.

I have used Prochlorperazine with some success 24 hours later. It was prescribed for my dizziness spells. It's a dopamine antagonist. My GP said it 'might' help with the tinnitus. I didn't know of KCC2 activation.

 

[Utdmad89]

I have used Prochlorperazine with some success 24 hours later. It was prescribed for my dizziness spells. It's a dopamine antagonist. My GP said it 'might' help with the tinnitus. I didn't know of KCC2 activation.

Were you on it for long? Could you get it again?

 

[Nick47]

Were you on it for long? Could you get it again?

Sporadic rather than daily use.

 

[Note]

Bear in mind hardly any of the Resveratrol will survive the digestion process. Maybe 5-10%.

"Extensive metabolism in the intestine and liver results in an oral bioavailability considerably less than 1%."

(Source)

 

[Note]

Do we know this since 2016?

→ Reactive Neurogenesis and Down-Regulation of the Potassium-Chloride Cotransporter KCC2 in the Cochlear Nuclei after Cochlear Deafferentation

 

[BB23]

The first human clinical trial for AXN-027 is set for the second half of 2024.

If there's a chance of a pill helping with tinnitus and/or visual snow, this could be it, assuming it passes all the clinical trials and gets approved. I say this because of benzodiazepines they work:

Benzodiazepines produce their effects by enhancing the binding of GABA to its receptor. GABA activates the chloride ion channel, allowing chloride ions to enter the neuron. The flow of chloride ions into the neuron hyperpolarizes and inhibits the neuron.

We know benzodiazepines supposedly help people with tinnitus and visual problems. However, the downregulation of the GABA receptors causes further inhibition issues.

This drug shouldn't cause that. Or I hope it shouldn't. I wonder if withdrawals are going to be a thing with it?

Keep an eye on this drug. If you need a magic pill that hits it where it hurts, this could be it.

 

[Note]

Unfortunately, they seem not to answer questions about tinnitus.

 

[Nick47]

The first human clinical trial for AXN-027 is set for the second half of 2024.

I quickly looked and couldn't see a trial setup or where it might be. Phase 1 would be for healthy patients, so it is a good opportunity for someone with tinnitus to participate. Once it gets to Phase 2, it will be epilepsy or whatnot all the way.

That's why if you are interested in a drug not being trialed for tinnitus, you need to hunt for Phase 1 trials. Once that boat has gone, there is a long wait until commercialization, with no anecdotal evidence to suggest whether or not you are following a losing horse.

 

[BB23]

Unfortunately, they seem not to answer questions about tinnitus.

I also sent them an email, but I haven't received a response yet.

I noticed that the company has a LinkedIn page stating that the human trials are scheduled for this year and listing their employees. Do you think it would be appropriate to reach out to them there and attach the paper by Arnaud Noreña? Or would that be considered rude?

 

[Nick47]

Do you think it would be appropriate to reach out to them there and attach the paper by Arnaud Noreña? Or would that be considered

It's absolutely appropriate. They are just normal folk.

 

[BB23]

From the man himself. He responds to emails, so maybe the Tinnitus Talk staff can interview him?

 

[Nick47]

From the man himself. He responds to emails, so maybe the Tinnitus Talk staff can interview him?

Respect to both of you! I think contacting researchers politely and with well-thought-out questions is always appropriate.

When I contacted Professor McNaughton, I also sent him research on Kv7.2/3 channels. Please don't assume they are aware of research outside their narrow focus. Often, they are not at all.

Bombarding them or criticizing them in messages? No.

As much grief as we might be in, any begging, pleading, and distressed emails will drive the researchers away.

You've carried out research and asked an intelligent question.

The first human clinical trial for AXN-027 is set for the second half of 2024.

You/us should wait for this Phase 1 to pop up. They will be looking for healthy volunteers for the Phase 1.