Prof. Tzounopoulos (University of Pittsburgh)

Update on Dr. Tzounopoulos... I had a rather long talk with Dr. Tzounopoulos yesterday (Friday) and will attempt to summarize the main points below. (Unfortunately I somehow 'lost/deleted' my first attempt, so this may be a bit briefer than it was going to be).

First up. My "instincts" about him seem to be accurate, and I am going to paste in the paragraph from the post above just to emphasize that point without having to re-phrase it:

As you will know from this thread, Team Trobalt has been working on numerous fronts to increase awareness of potentially helpful research, particularly in relation to the potassium channel modulators (Retigabine being one such compound) as potential "cures" for tinnitus - or at least serious contenders for helping T, versus the plethora of other patches and quasi-fixes out there...that in the end are mostly versions of 'learning to live with it'.
One of the simple goals for raising this awareness is to increase funding for those doing this type of research, and to get more 'happening' as quickly as possible.

This 'increased awareness' was one of the questions I had in mind when talking to Dr. Tzounopoulos. Likewise whether he was interested in participating in one of our TT "Q&A" sessions, or our promoting his work on Twitter and Facebook, etc.
His reply was at best "tepid"!
His reply to a "Q&A" was a clear "No".
His response to promoting what he was doing via Twitter and Facebook was..."It is public domain so I can't stop you, but I am going to focus on my research, period."
In relation to anything that smacked of medical, clinical aspects, trialing drugs, etc., etc. he was again, very clear. "No way I want to talk about that stuff, and it makes me very uncomfortable indeed. I am a researcher. That is what I know. That is what I do. That is all I will discuss."
My paraphrasing here, but if the message is not clear by now, it should be.

OK, so in relation to some other specific questions I was tasked with asking him.

The "zinc" DCN thing...Well I knew what his answer would be and apologized in advance for asking it. He had no comment on how, or what, or where, that may be useful to people taking zinc in any form or method. No idea, and not what his research was about. Again, too close to "medical" for comfort.

The long awaited "article" on new Kv7 derivatives...It is still not out yet and has still not been properly reviewed yet, and it may take more months before it is. And he likes it that way as it should be properly evaluated and checked before it goes out into the world. He has no interest in putting out some hasty report that has minor errors in it. Science needs to be the best it can be even if it takes longer than we had hoped to get it right....So, patience! He will let me know when it is close to publication. And no, he is not going to talk about any of it until it is public information, or darn close to it.

That's about the bones of it.

If I give the impression above in my report that the conversation was not quite "cordial", that is not exactly accurate, as we have a good rapport and he is willing to talk to me. However, I want to make it crystal clear that bringing up anything close to 'medical' or non lab rats/mice effects, kinda pisses him off. It is of course what we want to know most, so it's a tricky balancing act to try and get a little info but without pressing a thorn. So I'm sorry if I did not get more on all that, but there it is. And I 100% respect and support where he is coming from.

Dr. Tzounopoulos is one seriously passionate researcher and I'm damn glad he is working in a field that may help us with tinnitus! He does not have tinnitus himself, but he appreciates the suffering it causes and wants us to know he is not blind to that pain...but let him get on with those mice and the lab work. To my mind, the less interruptions he has with fluff and folderol, the faster he may come up with something remarkable for T...for us!

Best, Zimichael

 

Nice. Is he Greek?

 

New info on the drug SF0034 and how it works compared to Retigabine.

http://www.sciencedaily.com/releases/2015/06/150623180317.htm

 

I wonder when the FDA trials will start. Hopefully it won't give the same side effects as retigabine.

 

I just wish they hurry up a bit

 

@attheedgeofscience seems to have covered that in this post:

www.tinnitustalk.com/threads/scifluor-receives-us-patent-for-kcnq2-3-activator-to-treat-epilepsy-and-neurological-disorders.7743/page-2#post-120101

 

His most recent paper (on SF0034) was published on the 10th of June, if you haven't seen it (Zimichael, this is the voltage-gated Kv7 paper you were looking for) :

"...Behavioral studies demonstrated that SF0034 was a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 provides, not only a powerful tool for investigating ion channel properties, but, most importantly, it provides a clinical candidate for treating epilepsy and preventing tinnitus."​

[continue reading at: http://www.jneurosci.org/content/35/23/8829.abstract]​

A highlight from the contents that should be especially interesting:

"Compared with noise-exposed mice administered with vehicle (methylcellulose, 0.5%), injection of SF0034 reduced the percentage of noise-exposed mice that developed tinnitus (Fig. 8B; noise-exposed vehicle: 52.9%, 9 of 17; noise exposed SF0034: 17.6%, 3 of 17, p 0.05). "​

It also includes the synthesis, if you happen to have a chemistry lab handy and feel like making some yourself.

---

Aside,

I know the guy personally, describing him as "passionate" about his research is an understatement. He really truly loves what he does, and he's a great guy all around. But he is a molecular biologist and neuroscientist, not a medical doctor. I am absolutely certain he means absolutely no disrespect, he just really wants to focus on his work.

Keep in mind that in these contexts, there is not simply one professor or lab working a project. The work on SF0034 is in association with a specialist in total organic syntheses and intelligent drug design at the University of Pittsburgh and SciFluor, among many others. He is not personally handling the medical aspects of the project, but the fundamental neuroscience underpinning it.

My suggestion is to simply be patient. Science takes time. Keep in mind that unlike research intended to find a cure, Dr. Tzounopoulos' research is ultimately directed at understanding how and why tinnitus develops and the mechanisms behind its effects.

Remember, once tinnitus is understood at a fundamental level, the medical community will have the necessary tools to focus its efforts on drug development.

And more importantly to pharmaceutical companies and medical researchers, that understanding will slash R&D costs (hopefully) sufficiently to incentivize getting such drugs onto the market and available to those who need them.

 

@CriticallyDamped

Thanks for the info here, and yeah, despite being trashed well beyond the "dump' for past months, I did see this stuff and the "long awaited" paper I had been posting about for some time.
Immediately recognized the Sci-Fluor connection as had been attempting to contact them for ages too re SF0034 when was more active on Team Trobalt. (No replies to phone or email). That already established interconnection with Univ. of Pittsburgh was a bit of a surprise, but bodes well for more "rapid development" I believe, especially if they can piggy-back SF0034 off Retigabine as a derivative, re the "drug approval" run around.

Fully agree with you re his "passion", and his "non medical" stance. Tried to explain that many times too...The guy is a research fundi, and thank goodness, for as you say, if the T understanding gets nailed down then the 'cure' gets more in the cross-hairs.

Best, Zimichael

 

I looked through some of the channels.

KCNE4 suppresses Kv1.3 currents by modulating trafficking, surface expression and channel gating.
Solé L1, Roura-Ferrer M, Pérez-Verdaguer M, Oliveras A, Calvo M, Fernández-Fernández JM, Felipe A.
Author information

Abstract
Voltage-dependent potassium channels (Kv) play a crucial role in the activation and proliferation of leukocytes. Kv channels are either homo- or hetero-oligomers. This composition modulates their surface expression and serves as a mechanism for regulating channel activity. Kv channel interaction with accessory subunits provides mechanisms for channels to respond to stimuli beyond changes in membrane potential. Here, we demonstrate that KCNE4 (potassium voltage-gated channel subfamily E member 4), but not KCNE2, functions as an inhibitory Kv1.3 partner in leukocytes. Kv1.3 trafficking, targeting and activity are altered by the presence of KCNE4. KCNE4 decreases current density, slows activation, accelerates inactivation, increases cumulative inactivation, retains Kv1.3 in the ER and impairs channel targeting to lipid raft microdomains. KCNE4 associates with Kv1.3 in the ER and decreases the number of Kv1.3 channels at the cell surface, which diminishes cell excitability. Kv1.3 and KCNE4 are differentially regulated upon activation or immunosuppression in macrophages. Thus, lipopolysaccharide-induced activation increases Kv1.3 and KCNE4 mRNA, whereas dexamethasone triggers a decrease in Kv1.3 with no changes in KCNE4. The channelosome composition determines the activity and affects surface expression and membrane localization. Therefore, KCNE4 association might play a crucial role in controlling immunological responses. Our results indicate that KCNE ancillary subunits could be new targets for immunomodulation.

Kv2.1: a voltage-gated k+ channel critical to dynamic control of neuronal excitability.
Misonou H1, Mohapatra DP, Trimmer JS.
Author information

Abstract
Neurons use a variety of mechanisms to dynamically control their own signaling capabilities. Regulation of voltage-dependent K+ channel localization and function has long been recognized as a major mechanism to achieve dynamic regulation of intrinsic neuronal excitability in a number of mammalian and non-mammalian neurons. Our recent evidence, together with compelling data from other laboratories, suggests that in mammalian neurons the Kv2.1 channel may play an especially prominent role in determining intrinsic neuronal excitability. Kv2.1 is widely expressed in brain and composes the majority of delayed rectifier K+ current in pyramidal neurons in cortex and hippocampus, and is also widely expressed in interneurons. Dynamic modulation of Kv2.1 localization and function by a mechanism involving activity-dependent Kv2.1 dephosphorylation dramatically impacts intrinsic excitability of neurons. Here we review previous studies of Kv2.1 localization and function in neurons, and summarize recent work regarding dynamic regulation of these characteristics. We also discuss possible roles of the Kv2.1 channel in neuronal and network excitability.

Selective blockage of Kv1.3 and Kv3.1 channels increases neural progenitor cell proliferation.
Liebau S1, Pröpper C, Böckers T, Lehmann-Horn F, Storch A, Grissmer S, Wittekindt OH.
Author information

Abstract
The modulation of cell proliferation in neural progenitor cells (NPCs) is believed to play a role in neuronal regeneration. Recent studies showed that K(+) channel activity influenced cell proliferation. Therefore, we examined NPCs for K(+) channels and tested whether NPC self renewing can be modulated by synthetic K(+) channel modulators. The whole-cell K(+) current was partly K(+) dependent and showed a cumulative inactivating component. Two tetra-ethyl-ammonium ion (TEA)-sensitive K(+) currents with different voltage dependencies ( = 65 microm, E(50) = -0.3 +/- 1.3 mV and = 8 mm, E(50) = -15.2 +/- 2.8 mV) and an almost TEA-insensitive current were identified. Kaliotoxin blocked approximately 50% of the entire K(+) currents (IC(50) = 0.25 nm). These properties resembled functional characteristics of K(v)1.4, K(v)1.3 and K(v)3.1 channels. Transcripts for these channels, as well as proteins for K(v)1.3 and K(v)3.1, were identified. Immunocytochemical staining revealed K(v)1.3 and K(v)3.1 K(+) channel expression in almost all NPCs. The blockage of K(v)3.1 by low concentrations of TEA, as well as the blockage of K(v)1.3 by Psora-4, increased NPC proliferation. These findings underline the regulatory role of K(+) channels on the cell cycle and imply that K(+) channel modulators might be used therapeutically to activate endogenous NPCs.

Kv3.1/Kv3.2 conductance is necessary and kinetically optimized for high-frequency action potential generation.[5][7] Kv3.1 channels are important for the high-firing frequency of auditory and fast-spiking GABAergic interneurons, retinal ganglion cells; regulation of action potential duration in presynaptic terminals.[4][6]



This was from 2003

http://www.jneurosci.org/content/23/4/1133.full.pdf

AUT3, a Kv3.1 positive modulator, suppresses chronic noise-induced tinnitus in a rat model Jeremy G. Turner 1,2, Deb Larsen 1 , Charles Large 3 1 Southern Illinois University School of Medicine, Springfield IL, USA 2 Illinois College, Jacksonville IL USA 3 Autifony Therapeutics Limited, London, UK Kv3.1 channels are voltage-gated potassium channels that enable fast repolarization of the neuronal action potential, and are essential for the high frequency, high fidelity firing of neurons in the auditory brainstem and midbrain. Altered activity of these neurons has been implicated in the generation of tinnitus induced by noise exposure. Furthermore, loss of Kv3 channel function has been observed shortly after noise exposure, which may contribute to the maladaptive plasticity leading to the emergence of tinnitus. In the current study, 20 Long Evans rats (and 10 sham controls) were exposed to a unilateral 116 dB, 16 kHz octave-band noise for one hour in order to induce temporary hearing loss and chronic tinnitus. Thirty days after the noise exposure, a subset of approximately half of the noiseexposed rats demonstrated deficits in auditory gap processing, consistent with the presence of tinnitus. All 30 rats were administered 30 and 60 mg/kg of AUT3 (a Kv3.1 positive modulator) and vehicle in a counterbalanced order, with 48-hours washout between treatments. Both the 30 and 60 mg/kg doses of AUT3 abolished evidence of tinnitus, while the drug had no effect on the behavior of control animals or noise-exposed animals without tinnitus. These results suggest that AUT3 has potential in the treatment of chronic tinnitus associated with noise-induced hearing loss.

http://www.autifonytherapeutics.com/publications/Turneretal2013-TRI_final.pdf

MODULATION OF KV3.1B POTASSIUM CHANNEL PHOSPHORYLATION IN AUDITORY NEURONS BY CONVENTIONAL AND NOVEL PKC ISOZYMES*

http://www.jbc.org/content/early/2006/04/04/jbc.M512866200.full.pdf

This is about as much as I can find for now.

 

TZOUNOPOULOS UPDATE – Late August, 2015

I Have not been posting anything or even being on TT for quite a while, (see reasons below), but seeing as I was the original 'conversational link person' (via Team Trobalt) with Tzounopoulos I feel obliged to give an new update.

Once again, he has been busy. A new paper is in submission. Here's a summary:

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.

Clearly he is zeroing in on Kv7.2 and Kv7.3 again, which is his baillywick (the KCNQ group), and the mechanisms for what is happening with and causing tinnitus. I smell the whiff of maybe some genetic predisposition here, for that old question we have about why some people can blast themselves with sound forever and not get T, whereas others do it once or twice and get F'd for life with it. This "resilience" aspect. *[Which rings (sic.) true for me, seeing as my dad had tinnitus, and my only brother has tinnitus, and I have tinnitus. Bit of a 'predisposition' perhaps?!]

This article has not been published yet, so I will not be taking any questions on it. Just wanted to let you know that "more is in the works" from our rock star at U. Pitt.

In case the HCN stuff is new to some of the more serious folks following this research, there is a nice summary below and a few comments of my own, that may help – or confuse.

http://www.ncbi.nlm.nih.gov/books/NBK98137/

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels represent a unique class of voltage-gated ion channels. Initially characterized in the heart as “pacemaker” channels,1they are now understood to be an essential modulator of neuronal excitability in cortex, hippocampus, and thalamus.. Their diverse contributions to neuronal excitability stem from a constellation of unusual features: they are both voltage- and ligand-gated; they open with hyperpolarization of membrane potential rather than with depolarization; and in the principal neurons of cortex and hippocampus, they are localized almost exclusively to the apical dendrites where they exert a strong influence on the flow of excitatory synaptic inputs to the cell soma. Because of the influence of HCN channels on neuronal physiology, they also play an important role in epilepsy.

So yes, here we are in the AED class again (Anti-Epileptic Drugs) which is no surprise. Also note that these channels "activate" from hyperpolarization, which is kinda weird...as students of this stuff will note that that is when the neuronal firing (depolarization) is in a "beyond the rebound state", in a kind of 'overshoot shut down recovery mode' before it can 're-stabilize' into the baseline. In other words, back in the waiting, ready to fire again, 'polarized' state.
So, it seems like shit can happen at about any point in the 'firing curve' for screwed up "over excitation" (and thus T?!) to lock in somehow. Fantastic! Just pick your favorite researcher or neuro-dynamics theory...Sigh!

Oh, and a request just for me @Danny Boy...Can you please refrain from posting long, technical, Kv stuff straight from an article or abstract that just clutters up threads with more wordage that hardly anyone is going to understand anyhow. If you must, just throw in the hyperlink and let those who want to wade through it do it that way. I for one have given up on TT of late as most threads are just too full of stuff that is just "cud fodder" or chat miscellany. I don't have the desire or brain power to keep sifting all that irrelevant shit out of the serious topics. It's fine for "general support" threads, or PM's, but in the hard core T or T&H threads, it is a disservice IMO. Makes them too tedious, unreadable, and ultimately loses followers...like me! (And numerous others).

The 'serious' threads, I feel would be better served by personalized opinion or thoughts on the topic, with specific pasted extracts to illustrate a viewpoint being fine. I want a 'cure' for my bloody T. Wandering all over the universe, or going off topic like so many of the more 'scientific' threads have lately, just leads to exactly that...wandering around the universe. Waste of space.

Best, Zimichael

 

So it would seem restoring proper channel function quickly after intense noise exposure would prevent tinnitus for sticking around for longer (or forever).

I would imagine some who takes Trobalt quickly after getting T would have more chances of making it dissapear.

That's a bit of a stretch though (understatement of the year) coming from mice studies.

 

@Zimichael

Thank you for the update.
I know you said no questions but do you have any info on when this paper will finally be submitted?

 

You can read in it in the thread below: https://www.tinnitustalk.com/thread...ce-to-tinnitus-potential-drug-theraphy.10872/

 

So I have not heard anything recently about dr tzounopoulos after we got some very positive news that he successfully redesigned trobalt and/or retigabine into something that was way more powerful, and with what he thought was with way less side effects. I believe this was called sf0043. It might have a new name now.

Does anyone have any new updates or knows what the latest developments are?

 

Prof. Tzounopoulos, looking for a new employee, perhaps a good sign

https://jobs.sciencecareers.org/job/461538/systems-and-behavioral-auditory-neuroscience/

 

Yes, the man is still alive and working on Kv7.2/3 channels
http://phrc.pitt.edu/people/thanos-tzounopoulos

By the way... the brand new website of Pittsburgh Hearing Research Center is also worth your visit:
http://phrc.pitt.edu/

P.S.: New drug target is also sighted. Blocking those nasty H-channels in your brain seems also to be important next to opening those sturdy K-channels: http://phrc.pitt.edu/research

 

Are there any positive news regarding the studies of Thanos Tzounopoulos? As I understand, their main direction is the creation of a pharmacological drug based on GABA for tinnitus?

The internet does not have so much information, I, in fact, found nothing, except for a video from 4 years ago and the account Thanos Tzounopoulos on Twitter. Someone talked to him?

https://twitter.com/acousticthanos

 

@IvanRus

@DebInAustralia posted some updates this week here:

https://www.tinnitustalk.com/threads/in-loving-memory-of-danny-boy.30298/page-6#post-355132

—————

Thanos Tzounopoulos has replied today.

Here is his response.


"Very sad news… I am also devastated by this tragedy (Danny)…

Our studies continue toward discovering and developing scientific Kv7.2/3 channel openers.

Things are going well, and we have a couple of new compounds that will hopefully address retigabine's toxic effects...

If you decide to donate money to my research program, please visit my Center's site at:

http:/phrc.pitt.edu/support for how to get this done."


I will ask him to comment further on the new compounds that he is currently working on, and report anything relevant here.

 

Which is called earplugs.

 

I'm so upset that such important and unique studies are conducted with the financial support of almost exclusively volunteers and enthusiasts.

How can this be in the 21st century!? You need not that much money - a million dollars. I believe that everyone who can should donate to the research center of Professor Tzounopoulos.

This is a very serious researcher.

Am I right, in order to make a donation, I must go to this link https://eyeandear.thankyou4caring.org/DonateNow - select the amount, and in the "Designation" drop-down box select the project of Professor Tzounopoulos.

There are 2 options where it is worthwhile to donate - this is the "Pittsburgh Listening Research Center" and "Tinnitus Research".

Where better to donate?

Or is it better to donate to the professor himself?

 

Perhaps @DebInAustralia might ask the professor the best option to select?

 

Re: Further comments from Thanos

 

Pre clinical? They better hurry up.

 

God, they've been doing this since 2011. And the research is still at the preclinical stage ...

Apparently, they are too much hampered by corrupt officials from the FDA and a lack of funding.

To go through all the circles of hellish FDA checks, they need another 7 years.

 

Greek people have awesome sounding names.

 

So all this talk is great, but WHO DONATED to Dr. Tzounopoulos? I have just donated (which i will do from now on on a monthly basis). The research funds are drying up right now everywhere, and Dr. Tzounopoulos is clearly asking for our help. This is the time that we, together as a community must put actions in play and not just merely words on a forum.

This is the man who is working on an improved version of the one medicine that has worked for us but in its current form had too many side effects. Lets give him the support he needs and deserves. I have never heard about a more dedicated researcher who put all of his work out to help us. Let us all help this man back!

 

What item did you choose on the site with the donation? Have you selected the "Tinnitus Research" item on this page? (https://eyeandear.thankyou4caring.org/DonateNow)

I agree that we must help this study of the professor. Money is obviously the limiting factor, it slows down the process.

I do not know if funds collected by us can significantly affect something, but it is necessary to try.

I also thought about turning to @Ed209, in order to write to some fund, some philanthropist, so that he sent some money to the professor for these studies. In fact, we don't need that much money. But they are needed!

 

I will also donate something. Do i need to choose Tinnitus research right?

I‘ll start now donating monthly do different things, i was thinking also maybe giving to the TRI.