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

[StoneInFocus]

12-week 1000 mg/day supplementation of Quercetin results in a plasma concentration of about 2 µM, which is below the in vitro IC50 value of 27.32 µM of Quercetin for HCN2.

For Ivabradine, "the maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/ml."

22 ng per mL is 22.000 ng per L. The molecular weight of Ivabradine is 468,585 g/mol. According to this tool, 22.000 ng Ivabradine corresponds to 0.04695 µmol.

According to this study:

Ivabradine induced a time-dependent inhibition of hHCN4 with an IC50 of 0.5 μM.

Another study says:

Ivabradine efficiently blocks human HCN1 and HCN4 channels with the IC50 of 2.04 and 2.14 μM,
respectively.

This website says:

Ivabradine hydrochloride is a HCN channel blocker (IC50 is approximately 0.5 - 2.5 μM.

Question: If I'm not mistaken in my calculations and the plasma concentration of Ivabradine administrated 5 mg twice daily is indeed 10 to 50 times lower than the IC50 values of the HCN channels, how can Ivabradine exert its therapeutic effect?

Can we make conclusions about the effectiveness of a drug based on its IC50 value of the to be targeted receptor and the plasma concentrations reached by regular administration of that drug?

This study seems to suggest so:

Although quercetin and hesperetin have shown high reducing and antiradical activity, it should be taken into account that their bioavailability is around 20%; only this amount of orally administered dose reaches the bloodstream. Quercetin taken at 500 mg reaches a plasma concentration of about 1.4 μM, and hesperetin (500 mg) about 2.7 μM, so they were lower than the IC50 concentrations for which the activities were specified in our study.

TL;DR:

• The concentration of Quercetin after supplementation in the blood is lower than the reported IC50 value for the HCN2 channel.
• Assumption based on the excerpt from the above-mentioned study: Plasma concentrations need to match IC50 values in order to be therapeutically effective, ergo Quercetin will not be effective in blocking HCN2 channels.
• The plasma concentration of Ivabradine is also lower than the IC50 value of Ivabradine for HCN channels.

How does Ivabradine exert therapeutic effect? Possible options:

1. The assumption is wrong, plasma concentrations of a drug do not need to match IC50 values of the targeted receptors in order to be therapeutically effective. Question: In what ways can drugs be therapeutically effective if their reported reached plasma concentrations do not match the IC50/EC50 value for the targeted receptor?
2. Calculation went wrong.
3. The concept of the IC50 value means different things in different contexts. For example, maybe there is a difference in in vitro and in vivo IC50 values? So the cited IC50 values of themselves don't really tell us anything.
4. Other.

 

[Nick47]

@StoneInFocus, I had a look at the bioavailability of Quercetin. Unfortunately, after ingestion by humans, only 1-10% is bioavailable. Basically the rest is destroyed in the gut.

This is the issue with many supplements.

So you would need huge amounts to have an effect.

 

[BB23]

Apparently, Lamotrigine and this forum's favorite, Gabapentin are HCN channel agonists. I'm sorry my mind is very slow these days, does it mean we have to avoid these drugs?

HCN2 Channel-Induced Rescue of Brain Teratogenesis via Local and Long-Range Bioelectric Repair

 

[Nick47]

Apparently, Lamotrigine and this forum's favorite, Gabapentin are HCN channel agonists. I'm sorry my mind is very slow these days, does it mean we have to avoid these drugs?

Could you highlight and quote?

 

[BB23]

Could you highlight and quote?

From the paper "Endogenous HCN2 Channel Activators Rescue Nicotine-Induced Brain Defects Even After Delayed Treatment":

The induction of improvements in brain morphogenesis by transplants occurring well after teratogen exposure revealed that the effect is not simply prevention but also repair. To confirm this and establish a strategy that does not require tissue transplants, we next turned to human-approved ion channel activating drugs. To discover whether small molecule activation of endogenous HCN2 channels would be sufficient to rescue nicotine-induced brain defects, we used two well-known HCN channel activators: lamotrigine (LT) and gabapentin.

From the paper "The anticonvulsant lamotrigine enhances Ih in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy":

Lamotrigine is an HCN channel agonist and is known to enhance Ih in rodent cortical and hippocampal pyramidal neurons (Berger and Lüscher, 2004; Omrani et al., 2015; Poolos et al., 2002).

From a more recent paper "HCN channels and absence seizures":

Gabapentin is another anti-seizure medicine that was originally reported to increase Ih in hippocampal slices, but a more recent study showed that it selectively decreases HCN4 channel function (by hyperpolarizing their voltage-dependence of activation) in recombinant human HCN channels expressed in Xenopus oocytes and on native channels in spinal cord slices, with no effect on HCN1 and HCN2.

So, Gabapentin was thought to increase HCN activity, but turns out it decreases HCN4.

The funny thing is Gabapentin is also given to visual snow syndrome patients, and some do benefit from it but we all know it also causes visual snow syndrome itself.

In light of this, should we avoid Lamotrigine? I was thinking of using either that one or Keppra for my visual snow since both improve visual snow syndrome in a small number of people.

 

[Nick47]

From the paper "Endogenous HCN2 Channel Activators Rescue Nicotine-Induced Brain Defects Even After Delayed Treatment":

From the paper "The anticonvulsant lamotrigine enhances Ih in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy":

From a more recent paper "HCN channels and absence seizures":

So, Gabapentin was thought to increase HCN activity, but turns out it decreases HCN4.

The funny thing is Gabapentin is also given to visual snow syndrome patients, and some do benefit from it but we all know it also causes visual snow syndrome itself.

In light of this, should we avoid Lamotrigine? I was thinking of using either that one or Keppra for my visual snow since both improve visual snow syndrome in a small number of people.

It has no effect on HCN2.

 

[Chris C. Russo]

1. Ivabradine: While it primarily targets HCN4 channels, ivabradine has been reported to have some blocking effects on HCN2 channels.
   
   
2. ZD7288: ZD7288 is a non-selective HCN channel blocker and has been widely used in research to study the function of HCN channels, including HCN2.
   
   
3. Ifenprodil: Known as an NMDA receptor antagonist, ifenprodil has also been reported to block HCN1 and HCN4 channels.
   
   
4. Ivabradine analogs: Some research has focused on developing analogs of ivabradine with improved selectivity for HCN channels.
   
   
5. Cs+ (Cesium ions): Cesium ions are known to block HCN channels, and their use in experimental settings has provided insights into channel function.
   
   
6. Lamotrigine: While primarily known as an antiepileptic drug targeting voltage-gated sodium channels, lamotrigine has been reported to block HCN channels, including HCN2.
   
   
7. 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS): DIDS is a compound that has been used to inhibit various ion channels, including HCN channels.
   
   
8. Ethylmethyl 4-aminobenzoate (toluene-4-sulfonamide, EMA-TS): This compound has been reported to block HCN channels, including HCN2.
   
   
9. Lidocaine: Lidocaine is a local anesthetic that has been reported to inhibit HCN channels, although it may have broader effects on ion channels.
   
   
10. Cilobradine: Similar to ivabradine, cilobradine is a selective HCN channel blocker that has been investigated for its effects on heart rate.
    

 

[StoneInFocus]

1. Ivabradine: While it primarily targets HCN4 channels, ivabradine has been reported to have some blocking effects on HCN2 channels.
   
   
2. ZD7288: ZD7288 is a non-selective HCN channel blocker and has been widely used in research to study the function of HCN channels, including HCN2.
   
   
3. Ifenprodil: Known as an NMDA receptor antagonist, ifenprodil has also been reported to block HCN1 and HCN4 channels.
   
   
4. Ivabradine analogs: Some research has focused on developing analogs of ivabradine with improved selectivity for HCN channels.
   
   
5. Cs+ (Cesium ions): Cesium ions are known to block HCN channels, and their use in experimental settings has provided insights into channel function.
   
   
6. Lamotrigine: While primarily known as an antiepileptic drug targeting voltage-gated sodium channels, lamotrigine has been reported to block HCN channels, including HCN2.
   
   
7. 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS): DIDS is a compound that has been used to inhibit various ion channels, including HCN channels.
   
   
8. Ethylmethyl 4-aminobenzoate (toluene-4-sulfonamide, EMA-TS): This compound has been reported to block HCN channels, including HCN2.
   
   
9. Lidocaine: Lidocaine is a local anesthetic that has been reported to inhibit HCN channels, although it may have broader effects on ion channels.
   
   
10. Cilobradine: Similar to ivabradine, cilobradine is a selective HCN channel blocker that has been investigated for its effects on heart rate.

Do you have a source for these claims?

From the paper "The anticonvulsant lamotrigine enhances Ih in layer 2/3 neocortical pyramidal neurons of patients with pharmacoresistant epilepsy":

Lamotrigine is an HCN channel agonist and is known to enhance Ih in rodent cortical and hippocampal pyramidal neurons (Berger and Lüscher, 2004; Omrani et al., 2015; Poolos et al., 2002).

So Lamotrigine is both an HCN channel opener (agonist) and an HCN channel blocker? This doesn't add up.

 

[BB23]

So Lamotrigine is both an HCN channel opener (agonist) and an HCN channel blocker? This doesn't add up.

Sorry for the confusion I caused. But as I'm trying to do research on our condition, I stumble upon many, many papers and the information they present often conflict with one another. Such was the case with Gabapentin. At first they reported it increased the HCN activity, now they say it decreases HCN4 with no effects on other channels. I wonder what it is going to be 5 years from now, maybe they'll say it antagonizes all channels lol.

I already have ZERO trust in the pharmaceutical industry and I have come to terms with most doctors being very very... clueless. Since their treatment resulted in me suffering from this ailment as well as many others here on Tinnitus Talk.

As it turns out, those papers we post aren't so different when it comes to presenting correct data.

When it comes to Lamotrigine, the first papers I found said it opens the HCN channels which in turn increases Ih currents. Now, the guy above you posts conflicting information.

Here is yet another paper from yesteryear, saying exactly this with a schematic explaining the details below the quote:

Surprisingly, we found that LTG had no effects on either the midpoint voltage of activation or maximal tail current density of either HCN1 or HCN2 channels; LTG also had no effects when HCN1 was coexpressed with its auxiliary subunit TRIP8b. In contrast, under the same conditions, LTG exerted its expected inhibitory effect on NaV1.5 sodium channel currents. These results clearly show that LTG is not a direct activator of HCN channels and suggest that any effects reported in neurons are the result of indirect regulation of Ih, perhaps secondary to Na+ channel block.

But that quote makes me hopeful. It shows me messing around with Sodium channels also does something to HCN currents. Previously Prof. Tzounopoulos reported something similar with potassium channels too. So messing around with Sodium and Potassium channels in turn have an effect on HCN channels. From his studies:

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

 

[StoneInFocus]

When it comes to Lamotrigine, the first papers I found said it opens the HCN channels which in turn increases Ih currents. Now, the guy above you posts conflicting information.

Agreed.

I believe @Chris C. Russo imprudently copied his message from Bing Chat and presented it as his own work, which of course causes confusion.

In this paper, Lamotrigine is also called an HCN channel agonist. I think this settles the debate for now.

 

[StoneInFocus]

Ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Nav1.5 sodium channels at therapeutically relevant concentrations.

The Bradycardic Agent Ivabradine Acts as an Atypical Inhibitor of Voltage-Gated Sodium Channels

Ivabradine acts as an atypical inhibitor of VGSCs. Ivabradine inhibited VGSCs in a voltage- and frequency-dependent manner, but did not alter voltage-dependence of activation and fast inactivation, nor recovery from fast inactivation. Cardiac (Nav1.5), neuronal (Nav1.2), and skeletal muscle (Nav1.4) VGSC isoforms were inhibited by ivabradine within the same concentration range.

Question:

• Relevance sodium channel inhibition to diabetic neuropathic pain/tinnitus alleviating properties Ivabradine?

 

[BB23]

Ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Nav1.5 sodium channels at therapeutically relevant concentrations.

The Bradycardic Agent Ivabradine Acts as an Atypical Inhibitor of Voltage-Gated Sodium Channels

Ivabradine acts as an atypical inhibitor of VGSCs. Ivabradine inhibited VGSCs in a voltage- and frequency-dependent manner, but did not alter voltage-dependence of activation and fast inactivation, nor recovery from fast inactivation. Cardiac (Nav1.5), neuronal (Nav1.2), and skeletal muscle (Nav1.4) VGSC isoforms were inhibited by ivabradine within the same concentration range.

Question:

• Relevance sodium channel inhibition to diabetic neuropathic pain/tinnitus alleviating properties Ivabradine?

I'd suggest you research Lamotrigine and the upcoming NBI-921352 by Xenon Pharmaceuticals if you want to go with sodium channel blockers.

Through what mechanism Ivabradine could be useful for tinnitus, nobody knows. But Lamotrigine works on the same sodium channels, and some people are successful with it, while others report horrible stuff (both anecdotal, you can find some reports here on Tinnitus Talk as well as on Reddit.)

Lamotrigine also modulates Serotonin so might be dangerous. Some people report increased visual symptoms while on it, yet it also reduces/eliminates visual snow for others, both confirmed in this paper. And as you already know, it increases HCN2 currents.

Reportedly Lamotrigine is an inhibitor of voltage-gated sodium channels (Nav), blocking human Nav1.2, Nav1.5, and Nav1.8 with IC50 values of 10, 62, and 96 μM.

It also modifies Nav1.4 according to this paper.

So make your own deductions based on what Lamotrigine does I guess.

 

[StoneInFocus]

Through what mechanism Ivabradine could be useful for tinnitus, nobody knows.

So make your own deductions based on what Lamotrigine does I guess.

You don't think HCN2 channel blockage is a major contributor to Ivabradine's tinnitus alleviating properties?

What do you think is there to be deduced?

 

[BB23]

You don't think HCN2 channel blockage is a major contributor to Ivabradine's tinnitus alleviating properties?

What do you think is there to be deduced?

Your first question was about the sodium blockage properties of Ivabradine, and its relevancy to alleviating tinnitus.

Lamotrigine also blocks the same sodium channels and alleviates tinnitus in some, so the sodium channel blockage of Ivabradine ALSO may be relevant to alleviating tinnitus on top of its already existing HCN2 properties. Dual action is what I mean. But no studies has been done on this so it is just my deduction.

The difference between them is that Lamotrigine also has action on Serotonin and Glutamate.

I wouldn't be a guinea pig for Ivabradine though, sounds very dangerous.

 

[StoneInFocus]

Your first question was about the sodium blockage properties of Ivabradine, and its relevancy to alleviating tinnitus.

Lamotrigine also blocks the same sodium channels and alleviates tinnitus in some, so the sodium channel blockage of Ivabradine ALSO may be relevant to alleviating tinnitus on top of its already existing HCN2 properties. Dual action is what I mean. But no studies has been done on this so it is just my deduction.

The difference between them is that Lamotrigine also has action on Serotonin and Glutamate.

I wouldn't be a guinea pig for Ivabradine though, sounds very dangerous.

Thanks for clarifying what you mean.

To what extent do you think that the tinnitus effects of Lamotrigine are a function of its serotonergic and glutamatergic activity versus its sodium channel blockage?

Couldn't Lamotrigine's HCN2 opening capabilities contribute to its tinnitus effects too?

What I'm questioning is whether we can really make any conclusions about the role of these sodium channels in the tinnitus alleviating properties of Ivabradine based on the effects of Lamotrigine on tinnitus, because:

• Lamotrigine works on multiple receptors and neurotransmitters besides Nav1.5, Nav1.2 and Nav1.4.
• You have not really specified whether Lamotrigine at therapeutically relevant concentrations has the same effect on these sodium channels as Ivabradine does at therapeutically relevant concentrations.

Looking forward to hearing your thoughts.

I wouldn't be a guinea pig for Ivabradine though, sounds very dangerous.

I'm not lining up to try Ivabradine either, but please provide evidence that the drug is 'dangerous' if you follow the guidelines.

 

[BB23]

I'm not lining up to try Ivabradine either, but please provide evidence that the drug is 'dangerous' if you follow the guidelines.

I mean, a user trialled Ivabradine here a couple pages back, and he reported bad side effects from it. Here's a paper documenting concerns over Ivabradine causing similar problems.

From the above paper:

No solid clinical data support its antiarrhythmic effects, and there are concerns over its possible QT-prolonging effects and related risk of TdP. Furthermore, there is a well-documented increased incidence of AF with ivabradine, although some evidence indicates that ivabradine in combination with beta-blockers may reduce the risk of AF.

With Lamotgirine, I did lots of research because of my HPPD/VSS, I know it causes LOTS of side effects from flesh eating diseases (Steven-Johnson Syndrome) to increased palinopsia and trailing. One other side effect being heart arrhythmias, based on its sodium channel blocking properties, based on this paper.

Here is another paper on Lamotrigine. It says Lamotrigine is a weak Nav1.5 blocker. This channel is present in the heart and causes heart related effects. The conclusion is:

In fact, at therapeutic doses, the observed electrophysiological properties of lamotrigine do not result in alteration of cardiac conduction that could be of clinical concern, as assessed by the evaluation of PR and QRS interval in a TQT study in healthy subjects. Yet, there is agreement that class Ib-like agents may carry risks for pro-arrhythmia, particularly in higher risk patients with clinically important structural or functional heart disease. Therefore, considering a lack of unequivocal clinical data against it, such caution should be considered for these higher risk subpopulations who are indicated lamotrigine for the treatment of epilepsy or bipolar disorder.

I also found out Ivabradine blocks heterologously expressed Nav1.5 channels with an IC50 of 30 µM, that is two times stronger than Lamotrigine's IC50 I posted above. I couldn't find info on IC50 values of other channels.

Just Google Lamotrigine or Ivabradine, heart, reddit or some other site name like drugs.com to see how people were affected by these meds. There are some bad ones.

Couldn't Lamotrigine's HCN2 opening capabilities contribute to its tinnitus effects too?

You are right. I absolutely think this is why it triggers tinnitus in some patients. Also, remember that Serotonin, through HCN channels, excites fusiforms cells, which sounds like a recipe for disaster for tinnitus sufferers, I would never touch it knowing what I know, yet some people improved on it.

What I'm questioning is whether we can really make any conclusions about the role of these sodium channels in the tinnitus alleviating properties.

We can't make any conclusions at all. Just guesses based on what we read. I can't answer your other questions regarding this. Need lots of guinea pigs to try these drugs.

To what extent do you think that the tinnitus effects of Lamotrigine are a function of its serotonergic and glutamatergic activity versus its sodium channel blockage?

No real evidence, but I don't think its serotonergic activity does anything positive for tinnitus. When I was doing research on VSS and HPPD, on those boards people came to the conclusion it works since it modulates Glutamate and by slowing down the brain by blocking sodium channels, since the GABAergic properties of the brain have been lost. Similar story with Keppra.

So, if it works for you when it comes to tinnitus, I'd say it is because of these two actions over its serotonergic properties. All assumptions though.

Strangely, Klonopin (Clonazepam) also works for VSS/HPPD to great extend, much like it works for tinnitus patients...

 

[StoneInFocus]

Ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Nav1.5 sodium channels at therapeutically relevant concentrations.

I just opened the paper, it says that "we determined an IC50 value of 30 µM for the inhibition of human Nav1.5 by ivabradine under our experimental conditions. This is an order of magnitude higher than the IC50 values reported [elsewhere] for HCN channel inhibition."

So how therapeutically relevant is Nav1.5 channel blockage by Ivabradine, really?

I mean, a user trialled Ivabradine here a couple pages back, and he reported bad side effects from it. Here's a paper documenting concerns over Ivabradine causing similar problems.

Thus far I have read some anecdotes of Ivabradine causing unpleasant side effects. The fact of an 'increased incidence of AF' alone does not practically tell us anything about the risks of taking Ivabradine.

But I agree that Ivabradine is definitely a sub-optimal treatment option for tinnitus.

 

[ma7555]

Could this be why Lidocaine works for tinnitus but nobody knows why? Almost all papers admit significant reduction or total resolution of tinnitus under IV Lidocaine but can not attribute it to its most well known MoA on sodium channels since other sodium channel blockers do not work.

1. Lidocaine Inhibits HCN Currents in Rat Spinal Substantia Gelatinosa Neurons
2. Local Anesthetic Inhibits Hyperpolarization-Activated Cationic Currents
3. Cation and voltage dependence of lidocaine inhibition of the hyperpolarization-activated cyclic nucleotide-gated HCN1 channel
4. Hyperpolarization-activated Cyclic Nucleotide-gated Channels May Contribute to Regional Anesthetic Effects of Lidocaine

 

[Note]

Not sure if I should take abnormally high doses of Quercetine for a week or two. It seems that bioavailability is best for Liposomal Quercetine.

 

[StoneInFocus]

From LinkedIn:

Maybe they will drop some new information on March 7?

Not sure if I should take abnormally high doses of Quercetine for a week or two. It seems that bioavailability is best for Liposomal Quercetine.

I have been using Quercetin Phytosome 500 mg once daily from Healthy Origins for about a month now, I think. I haven't noticed any effect, but I am taking a shit-ton of other supplements and medications as well.

 

[HighleyTall]

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. 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.

I still have a jar of Quercetin I bought during the pandemic because they used it as a treatment. Never touched it. I will start today, 3 x 400mg.

@StoneInFocus, I had a look at the bioavailability of Quercetin. Unfortunately, after ingestion by humans, only 1-10% is bioavailable. Basically the rest is destroyed in the gut.

This is the issue with many supplements.

So you would need huge amounts to have an effect.

It probably doesn't even pass the blood labyrinthine barrier... Damn!

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 :/

Too bad it wasn't a success. How long did you take Ivabradine for?

 

[Muggumbo]

From LinkedIn:

View attachment 56503

Maybe they will drop some new information on March 7?

I have been using Quercetin Phytosome 500 mg once daily from Healthy Origins for about a month now, I think. I haven't noticed any effect, but I am taking a shit-ton of other supplements and medications as well.

I get migraines and have tinnitus, so this would be a double whammy for me lol.

 

[Nick47]

Maybe they will drop some new information on March 7?

Not unless they have a TARDIS!

 

[StoneInFocus]

I get migraines and have tinnitus, so this would be a double whammy for me lol.

You should try Flunarizine.

 

[Nick47]

Recent interview with Professor Peter McNaughton:

My entry into this field was just by chance – I was working on chronic pain and wondered whether some of the advances that my group had made would also apply to tinnitus. So far this has turned out to be correct.

(Source)

 

[Muggumbo]

Recent interview with Professor Peter McNaughton

Very good find. Thanks for sharing this.

 

[HighleyTall]

I believe Professor Peter McNaughton is getting close. After 20 years of tinnitus, it is starting to feel like chronic pain. I can take the sound; I always used to adapt. However, my tinnitus has turned into chronic pain in the posterior temporal regions, resulting in headaches in the frontal region. I continuously have sensations all over my skull and face.

But it can take years to develop a medicine.

 

[Note]

Maybe they will drop some new information on March 7?

Any news?

 

[StoneInFocus]

Any news?

I did not attend.

 

[Nick47]

Any news?

Why don't you email him at Kings College London? Or contact the RNID, who sponsor the research?

Then you can give something to us.