Pitt Team Identifies Cause of Resilience to Tinnitus, Potential Drug Theraphy

[Roger Wolf]

Came across this article...

http://www.eurekalert.org/pub_releases/2015-08/uops-pti082715.php

PITTSBURGH, Aug. 27, 2015 - Researchers have identified in an animal model the molecular mechanisms behind resilience to noise-induced tinnitus and a possible drug therapy that could reduce susceptibility to this chronic and sometimes debilitating condition. The findings by a team from the University of Pittsburgh School of Medicine were published online in the journal eLife.

Tinnitus is typically induced by exposure to loud noise and causes whistling, clicking, roaring and other phantom sounds. It is estimated that 5 to 15 percent of Americans suffer from tinnitus, said Thanos Tzounopoulos, Ph.D., associate professor and member of the auditory research group in the Department of Otolaryngology, Pitt School of Medicine, where he also holds the auditory physiology endowed chair.

The study results build on previous research in mouse models demonstrating that tinnitus is associated with hyperactivity of dorsal cochlear nucleus (DCN) cells, which fire impulses even when there is no actual sound to perceive. The team's work has shown that this hyperactivity is caused by a reduction in tiny channels, called KCNQ channels, through which potassium ions travel in and out of the cell. Based on this finding, KCNQ channel activators have emerged as clinical candidates for preventing the development of tinnitus.

"However, a significant percentage of people are exposed to loud sounds and never develop tinnitus, and there was little known about why that is. That's what we set out to examine in this study," Dr. Tzounopoulos said.

This newest study found that mice that are exposed to loud noise but do not develop tinnitus show a transient reduction in KCNQ2/3 channel activity, which is followed by a recovery of KCNQ2/3 activity and a reduction in hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity, another channel through which positively charged ions travel in and out of the cell.

The investigators believe a combination of drugs that enhance KCNQ2/3 channel activity and reduce HCN channel activity could promote resilience and reduce susceptibility to tinnitus.

"We have already developed novel activators of KCNQ2/3 channels. The next step, in collaboration with Dr. Peter Wipf, a medicinal chemist from the University of Pittsburgh, is to develop specific blockers of HCN channels," Dr. Tzounopoulos said.

###

Co-authors of the paper are Shuang Li, Ph.D., and Bopanna I. Kalappa, Ph.D., of Pitt's Department of Otolaryngology. The project was funded by the Department of Defense Peer Reviewed Medical Research Program grant PR093405, Joint Warfighter Medical Research Program grant W81XWH-14-1-0117 and by the National Institutes of Health grant R01-DC007905.

 

[derpytia]

Uh.... anyone wanna explain it to me in layman's terms? I'd appreciate it!

 

[Danny Boy]

Uh.... anyone wanna explain it to me in layman's terms? I'd appreciate it!

It's basically that SF drug. It's basically trobalt but is more selective vs trobalt as trobalt work on 5 different channels, hence the side-effects. SF works on KV7.2 and KV7.3. Basically, it'll be a more potent version of trobalt with less side-effects. However, they aren't even in phase 1 yet and Autifony will be out sooner and really if Autifony works it may be pointless for their drug to be released for tinnitus (They are epilepsy first). Then again, I know that the KV7.2 and 3 channels are to do with excitability, so it could work even better than Autifony, but really we won't know until they test it on people.

KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability.

 

[passerby]

It's basically that SF drug. It's basically trobalt but is more selective vs trobalt as trobalt work on 5 different channels, hence the side-effects. SF works on KV7.2 and KV7.3. Basically, it'll be a more potent version of trobalt with less side-effects. However, they aren't even in phase 1 yet and Autifony will be out sooner and really if Autifony works it may be pointless for their drug to be released for tinnitus (They are epilepsy first). Then again, I know that the KV7.2 and 3 channels are to do with excitability, so it could work even better than Autifony, but really we won't know until they test it on people.

It's basically not about drugs (at least not specifically SF0034), but about identifying ion channels responsible for the induction of tinnitus. As a specific note is the involvement of a new channel, HCN.

• "Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus." (Abstract, page 2)
• "...we propose that a combination of drugs that enhance KCNQ2/3 and reduce HCN channel activity represents a potent therapeutic approach that will enhance resilience and reduce vulnerability to tinnitus." (page 20)

The above quotes express the therapeutic angle proposed to prevent and possibly treat tinnitus. It should be noted however that the GAP detection model has been criticized in scientific circles: the results produced may not be replicable in humans. Human testing is therefore an important step (for proof-of-concept).

The literature also introduces new concepts such as "resilience to tinnitus" and "vulnerability to tinnitus" (important new terms).

Full text attached.

a (concerned) passerby

 

[Silvio Sabo]

It's basically that SF drug. It's basically trobalt but is more selective vs trobalt as trobalt work on 5 different channels, hence the side-effects. SF works on KV7.2 and KV7.3. Basically, it'll be a more potent version of trobalt with less side-effects. However, they aren't even in phase 1 yet and Autifony will be out sooner and really if Autifony works it may be pointless for their drug to be released for tinnitus (They are epilepsy first). Then again, I know that the KV7.2 and 3 channels are to do with excitability, so it could work even better than Autifony, but really we won't know until they test it on people.

KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability.

It will never be pointless for them to release yet another drug, even if Autifony works. The more variation of drugs there are the better the chance that we can treat people. For every drug you will always have non-responders that won't be helped so having options is vital.

 

[Danny Boy]

It will never be pointless for them to release yet another drug, even if Autifony works. The more variation of drugs there are the better the chance that we can treat people. For every drug you will always have non-responders that won't be helped so having options is vital.

I meant that having less side-effects is important. We don't know what side-effects KV7.2 does nor do we know the side-effects of KV7.3. But I will say that, according to Autifony the KV3 channels are the most important for tinnitus. The SF drug is being designed for epilepsy first and foremost.

 

[nills]

The reason why some SSRI`s work for some people and not for others is because the sub coding of the 5-ht receptors differs for each person. Some drugs might work on receptors that don`t do anything for one person but are the best bet for another ... I hope the story is different with these drugs and the receptor sites they target.

 

[Twitch]

Abstract

Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in DCN fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.

Full article: http://elifesciences.org/content/elife/early/2015/08/27/eLife.07242.full.pdf

I spent 15-20 minutes reading and skipped over some sections but in summary, it talks about how tinnitus starts off with reduction in KCNQ2/3 channel activity. Those lucky 'resilient' folk who encounter temporary tinnitus , likely do so because their KCNQ2/3 channel activity returns to normal after 7 days.

Those of us who are less fortunate, the reduced KCNQ2/3 channel activity is the beginning of a chain of events that causes neural plasticity resulting & chronic tinnitus. Deriving from the research, it appears that more research needs to be done on what changes occur elsewhere 7 days after the the reduced KCNQ2/3 channel activity which results in chronic tinnitus.

The article also talks about the use of retigabine and its improved iteration, SF0034 claiming taking these drugs 30 minutes or up to 4 days after acoustic trauma until day 7 after exposure can result in resilience aka stopping tinnitus from becoming chronic as was found most of the mice models they tested.

Although this doesn't really offer much hope for those of us with chronic tinnitus, it does help explain how tinnitus becomes chronic in a mice model. Kudos to Dr. Tzounopoulos and co

 

[markoana]

Abstract

Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in DCN fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.

Full article: http://elifesciences.org/content/elife/early/2015/08/27/eLife.07242.full.pdf

I spent 15-20 minutes reading and skipped over some sections but in summary, it talks about how tinnitus starts off with reduction in KCNQ2/3 channel activity. Those lucky 'resilient' folk who encounter temporary tinnitus , likely do so because their KCNQ2/3 channel activity returns to normal after 7 days.

Those of us who are less fortunate, the reduced KCNQ2/3 channel activity is the beginning of a chain of events that causes neural plasticity resulting & chronic tinnitus. Deriving from the research, it appears that more research needs to be done on what changes occur elsewhere 7 days after the the reduced KCNQ2/3 channel activity which results in chronic tinnitus.

The article also talks about the use of retigabine and its improved iteration, SF0034 claiming taking these drugs 30 minutes or up to 4 days after acoustic trauma until day 7 after exposure can result in resilience aka stopping tinnitus from becoming chronic as was found most of the mice models they tested.

Although this doesn't really offer much hope for those of us with chronic tinnitus, it does help explain how tinnitus becomes chronic in a mice model. Kudos to Dr. Tzounopoulos and co

Not just for us, but for all who will get t. in next 5 yaers. They will be chronic until this Pittsburgh stuff from Greek guys goes to the market... So, it looks like all hopes are in aut63

 

[Twitch]

Autifony are ahead in that their AUT00063 is at phase 2. It's also worthy to note that both drug target different areas. AUT00063 targets Kv3 channels whereas SF0034 targets Kv7.2/3 channels. Would be interesting to see how a concoction of both works

 

[Bertman]

Would be interesting to see how a concoction of both works

Now that sounds like a silence party to me

 

[markoana]

Autifony are ahead in that their AUT00063 is at phase 2. It's also worthy to note that both drug target different areas. AUT00063 targets Kv3 channels whereas SF0034 targets Kv7.2/3 channels. Would be interesting to see how a concoction of both works

Maybe combination of those 2 will be fatal for most of t suffers... But we do not have still any information abt SF34, dates of trials, nothing...I doubt it can come to market before 2023...and one more bad side is that is gonna be an aepileptic drug at the firts place :/

 

[locoyeti]

Abstract

Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in DCN fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.

Full article: http://elifesciences.org/content/elife/early/2015/08/27/eLife.07242.full.pdf

I spent 15-20 minutes reading and skipped over some sections but in summary, it talks about how tinnitus starts off with reduction in KCNQ2/3 channel activity. Those lucky 'resilient' folk who encounter temporary tinnitus , likely do so because their KCNQ2/3 channel activity returns to normal after 7 days.

Those of us who are less fortunate, the reduced KCNQ2/3 channel activity is the beginning of a chain of events that causes neural plasticity resulting & chronic tinnitus. Deriving from the research, it appears that more research needs to be done on what changes occur elsewhere 7 days after the the reduced KCNQ2/3 channel activity which results in chronic tinnitus.

The article also talks about the use of retigabine and its improved iteration, SF0034 claiming taking these drugs 30 minutes or up to 4 days after acoustic trauma until day 7 after exposure can result in resilience aka stopping tinnitus from becoming chronic as was found most of the mice models they tested.

Although this doesn't really offer much hope for those of us with chronic tinnitus, it does help explain how tinnitus becomes chronic in a mice model. Kudos to Dr. Tzounopoulos and co

this is a good synopsis, but I think the HCN channel involvement is pretty exciting.

I found two quotes to be informative:

"our results suggest that it is the recovery in KCNQ2/3 channel activity, not the lack of reduction in KCNQ2/3 currents, which is linked with the resilience to tinnitus."

"biophysical changes that are associated with increases in fusiform cell spontaneous firing rates lead to tinnitus, while biophysical changes that maintain normal levels of spontaneous firing rates are associated with tinnitus resilience. "

this is a cool image:

this raises the question of whether it is sufficient merely to affect the KCNQ2/3 channels. perhaps concurrently taking a drug that lowers HCN activity might augment the process. incidentally there are drugs that affect HCN channels. I found just one post on this site from someone who had a reduction in their T with Tenex (Guanfarine), which is a HCN modulator:
https://www.tinnitustalk.com/threads/my-tinnitus-has-been-lower-since-taking-tenex.5281/

i am doing fine with my T, so I am not so motivated to try this experiment on myself, but it might be possible to take retigabine with Tenex and get some drastic improvement.

another quote:
" besides targeting KCNQ2/3 channel activators for preventing tinnitus, manipulations that hyperpolarize the fusiform cell RMP may also provide additional therapeutic approaches. "

another:
"we propose that coordinated plasticity of potassium and HCN channels may represent a general biophysical strategy for achieving neuronal homeostasis "*

*this quote is in the context of a general discussion about how homeostasis is achieved naturally.


aaaand finally:
"we propose that a combination of drugs that enhance KCNQ2/3 and reduce HCN channel activity represents a potent therapeutic approach that will enhance resilience and reduce vulnerability to tinnitus. Moreover, simultaneous pharmacological enhancement of KCNQ 2/3 and reduction of HCN channel activity is expected to act synergistically in stabilizing spontaneous firing rates in fusiform cells. This synergistic effect may in turn reduce the required concentration for each individual drug to exert its effect and therefore may lead to increased potency and reduced toxicity."
that last part means that if someone were brave enough to try this, they wouldn't need to take a lot of the drug. if i read this paper last year, i would seriously consider taking small dosages of each and see what the effect would be.

 

[ruben ruiz]

What about hyperacusis?

 

[markoana]

this is a good synopsis, but I think the HCN channel involvement is pretty exciting.

I found two quotes to be informative:

"our results suggest that it is the recovery in KCNQ2/3 channel activity, not the lack of reduction in KCNQ2/3 currents, which is linked with the resilience to tinnitus."

"biophysical changes that are associated with increases in fusiform cell spontaneous firing rates lead to tinnitus, while biophysical changes that maintain normal levels of spontaneous firing rates are associated with tinnitus resilience. "

this is a cool image:

View attachment 7658


this raises the question of whether it is sufficient merely to affect the KCNQ2/3 channels. perhaps concurrently taking a drug that lowers HCN activity might augment the process. incidentally there are drugs that affect HCN channels. I found just one post on this site from someone who had a reduction in their T with Tenex (Guanfarine), which is a HCN modulator:
https://www.tinnitustalk.com/threads/my-tinnitus-has-been-lower-since-taking-tenex.5281/

i am doing fine with my T, so I am not so motivated to try this experiment on myself, but it might be possible to take retigabine with Tenex and get some drastic improvement.

another quote:
" besides targeting KCNQ2/3 channel activators for preventing tinnitus, manipulations that hyperpolarize the fusiform cell RMP may also provide additional therapeutic approaches. "

another:
"we propose that coordinated plasticity of potassium and HCN channels may represent a general biophysical strategy for achieving neuronal homeostasis "*

*this quote is in the context of a general discussion about how homeostasis is achieved naturally.


aaaand finally:
"we propose that a combination of drugs that enhance KCNQ2/3 and reduce HCN channel activity represents a potent therapeutic approach that will enhance resilience and reduce vulnerability to tinnitus. Moreover, simultaneous pharmacological enhancement of KCNQ 2/3 and reduction of HCN channel activity is expected to act synergistically in stabilizing spontaneous firing rates in fusiform cells. This synergistic effect may in turn reduce the required concentration for each individual drug to exert its effect and therefore may lead to increased potency and reduced toxicity."
that last part means that if someone were brave enough to try this, they wouldn't need to take a lot of the drug. if i read this paper last year, i would seriously consider taking small dosages of each and see what the effect would be.

@Christian78 maybe this combination is gonna make your usage of trobalt extremly potent again!?

PS.Very informative @locoyeti!

 

[Christian78]

@Christian78 maybe this combination is gonna make your usage of trobalt extremly potent again!?

PS.Very informative @locoyeti!

There is possibility, but same is for autifony if people get resistant so they will be able to use it again...

 

[Christian78]

What about hyperacusis?

google it. oversensiti to certain sounds

 

[markoana]

There is possibility, but same is for autifony if people get resistant so they will be able to use it again...

Well about autifony it could be just guessing, maybe it will be long term use as cardio drugs, ephilepsy drugs, or it would be permanent reduction of sound (silence) after few months of usage. Who knows...

But this HCN channel involvement is very interesting, maybe he is more important than autifony team suppose... :/

 

[Nucleo]

This mechanism may explain how some people got great benefits from taking trobalt when their tinnitus was relatively in the early stages, such as @Mpt or @Danny Boy.

Perhaps a trial using Trobalt after acoustic trauma instead of going for prednisone or AM-101 would not be an outlandish idea.

 

[Danny Boy]

This mechanism may explain how some people got great benefits from taking trobalt when their tinnitus was relatively in the early stages, such as @Mpt or @Danny Boy.

Perhaps a trial using Trobalt after acoustic trauma instead of going for prednisone or AM-101 would not be an outlandish idea.

If only I had trobalt within the first week.

 

[Nucleo]

If only I had trobalt within the first week.

Yeah I don't think anyone on this planet tried trobalt this early. It's certainly less of a long shot than anything else out there.

 

[Danny Boy]

Yeah I don't think anyone on this planet tried trobalt this early. It's certainly less of a long shot than anything else out there.

Yep....I had this woman on facebook, she lived near me and I messaged her telling her I could cure her, she won't suffer anymore and I was willing to give her trobalt for free. I wanted to see if it had the potential to cure in the earliest stages. She didn't respond and blocked me. Odd really?

 

[Dutchy]

Correct me if i'm wrong but are these meds based on early-stage T? or are they also countering the effects of long-termT?.I mean is there a point where T is irreversible?.

 

[grate_biff]

Correct me if i'm wrong but are these meds based on early-stage T? or are they also countering the effects of long-termT?.I mean is there a point where T is irreversible?.

Well, I firmly believe, as @benryu have stated many times, that it really doesn´t matter how long you have had T for when it comes to drugs acting directly on the brain. eg KV modulators. There may be some inertia issues, meaning one has to stay on a drug for longer duration for the wanted effect, but other than that it really doesn´t matter. I can´t back this up scientifically, but no one can prove it´s not the case either.

 

[Carlos Galiano]

PNAS: Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus

http://www.pnas.org/content/110/24/9980.full.pdf?with-ds=yes

 

[Mithrandir]

Some ENT in France give prednisolone + AED (small dosage) for emergency treatment after acoustic trauma (with good results)...
But stupid Doctors & ENT (95%) give prednisolone+piracetam (useless for the last one)
That's a question of education...I take the prescription 4 months after my trauma...

The list is
1/neurontin
2/tegretol
3/depakine
4/topiramate
5/klonazepam


No trobalt cause I think they're afraid by it, trobalt is too young...

 

[RaZaH]

i am doing fine with my T

And this was achieved after your trial withTrobalt, right ?
Sry if I am confusing you with someone else

 

[jay-alex]

This makes sense to me. Treatments for tinnitus will probably be a combination of things, whether it be medication, rTMS, therapy, or some combination of these things.

I won't venture to say "this is it" but there may be some promise here. The findings here could also provide a possible explanation for why AUT0063 didn't pan out. Considering the relationship between the HCN and K+ channels, it could just be that both have to be tackled at once to treat tinnitus.

This also makes me wonder how SF0034 is doing. Maybe SF0034 or AUT0063 in combination with another new medication could provide a bit of relief in affected individuals.

 

[Philemon]

Just a short update :
I did try Trobalt + Guanfacine (a HCN modulator) together, as it is assumed in this thread that it could be beneficial. The experimentation unfortunately hasn't been beneficial at all, it basically changed nothing to my T. I've been able to taper up to 1200mg retigabine and 4mg guanfacine daily, and I took both drugs together for something like 6 weeks. Regarding side effects, I had bad constipation because of Guanfacine (was not so funny), but I didn't noticed any "interaction effect" (whether good or bad) between the 2 drugs in my case.
All in all, my T is still like I described it here : https://www.tinnitustalk.com/thread...-general-discussion.5074/page-219#post-147579 ... which means better than before I tooked trobalt, but not as good as it was during my first two months on the drug

Sorry for the double post with the main retigabine thread, but i thought like this it could be read by more people

 

[Jim51042]

Did anyone else try Trobalt + HCN modulator?