Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

Discussion in 'Research News' started by d'Wooluf, Jul 14, 2020.

    1. FGG
      No Mood

      FGG Member Hall of Fame

      Tinnitus Since:
      01/2019
      Cause of Tinnitus:
      Multi-factorial
      The SGN do degrade over time but it looks to be many, many decades to possibly never in most cases based on autopsy studies.

      They degrade relatively quickly in cats (for instance, which a lot of the early studies were done on :( ) but it turns out humans have extremely different spiral ganglion nerves:

      Impact of Morphometry, Myelinization and Synaptic Current Strength on Spike Conduction in Human and Cat Spiral Ganglion Neurons

      The human spiral ganglion: new insights into ultrastructure, survival rate and implications for cochlear implants

      I posted the autopsy study *somewhere* on this sight ages ago but I can't find it now. I believe one subject had been deaf since 20 and had normal SGN concentration at death at 80.

      Tl;dr: this is probably not a worry most people should have.
       
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    2. Tau
      Probing

      Tau Member

      Location:
      Europe
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      2019-Concert, 2021-headphones/acoustic trauma at 110dB,16kHz
      I am thinking of trying IV Zoledronate as my synaptopathic hearing loss is recent and I have no hair cell dysfunction.

      I will give an update in this thread if I do. My hearing loss is a bigger problem than tinnitus. I will consult with a few doctors and show them this paper. The problem is not getting the drug, it's weighing the pros and cons.
       
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    3. Mentos

      Mentos Member Benefactor

      Location:
      Cracow, Poland
      Tinnitus Since:
      03/2015
      Cause of Tinnitus:
      Noise induced, loud rock concert
      How did you confirm you have no hair cell dysfunction? I don’t believe there is a 100% reliable diagnostic method to determine that.
       
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    4. Tau
      Probing

      Tau Member

      Location:
      Europe
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      2019-Concert, 2021-headphones/acoustic trauma at 110dB,16kHz
      That's actually a good question. I guess it's more of a tentative conclusion based on the fact that I have perfect audiograms (and I confirmed that myself at home with all the in-between frequencies) and that my ABR and otoacoustic emissions tests are fine.

      I guess some of my IHCs could be dysfunctional or even completely dead. But seeing as synaptopathy happens first, I think trying to regrow the synapses is worth a shot.
       
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    5. Mentos

      Mentos Member Benefactor

      Location:
      Cracow, Poland
      Tinnitus Since:
      03/2015
      Cause of Tinnitus:
      Noise induced, loud rock concert
      Otoacoustic emission can confirm damage to hair cells, it cannot exclude it. In other words you may have ok otoacoustic emission results and still have damaged hair cells in the frequencies which are not measured (usually they sample 8 frequencies only).
       
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    6. Ali.sy

      Ali.sy Member

      Location:
      Deutschland
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      Headphones
      Can I buy Bisphosphonate medicine somewhere to try it?
       
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    7. Ali.sy

      Ali.sy Member

      Location:
      Deutschland
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      Headphones
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    8. Justin Mills

      Justin Mills Member

      Tinnitus Since:
      2 year
      Cause of Tinnitus:
      loud music
      "The repurposing of bisphosphonates shows promise in animal models for treating hidden hearing loss. At the present time, these drugs are not fit for hearing treatment because they have not yet been validated in human studies. For the purposes of treating metabolic bone disease—osteoporosis, etc.—they have demonstrated success. However, they are associated with some significant side effects and are absolutely contraindicated in pregnancy (they are known to cause birth defects). In time and with proper vetting, these techniques may ultimately be valuable treatments for a very common type of hearing loss."

      Source:
      Why Can't I Understand Speech in a Noisy Environment?

      According to the above quote from an ENT there's a question of whether it's worth the risk. There are probably people on this forum who know more about how effective something like this could be. Is it perhaps better to wait to see if there's an advancement with Pipeline Therapeutics' drug and Otonomy's OTO-413? Kind of biting the bullet. We wouldn't know how to use this drug, like what dose and how long and stuff like that. Although on the other hand, there's no doubt the study shows very promising results for something that can be applied systemically rather then locally injected:

      Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate
       
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    9. paul mclean

      paul mclean Member

      Tinnitus Since:
      2018
      Cause of Tinnitus:
      falling asleep with headphones in on loud
      Yes you can. I am going to try Zoledronic acid soon. Going to do 0.5 mg IV infusion. i believe it'll work for my cochlear synaptopathy. Worth a shot. There is no need to use the full dose in my opinion (4 mg or 5 mg) as those are intended for osteoporosis. The reason why systemic administration works of Zoledronic acid is because it is the most potent Bisphosphonate (5000 to 1) and it has a high affinity for bone. The region of the cochlear is obviously surrounded by a lot of bone. It is also long lasting, its effects can last anywhere from 12-24 months and sometimes even longer.

      I've had my synaptopathy since October 2018 after falling asleep with headphones on for 13 hours on loud. So it's been a little bit of time but there is evidence suggesting SGNs stay intact for multiple years. I'll report back with my results. If I can regenerate at least some synapses I'll be happy. I'm doing the lowest dose possible just to try decrease any adverse reactions.
       
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    10. GregCA
      Jaded

      GregCA Member Benefactor Hall of Fame

      Tinnitus Since:
      03/2016
      Cause of Tinnitus:
      Otosclerosis
      Let us know how it goes. Bisphosphonates have been looked into as a treatment for otosclerosis. There are a few studies available for your perusal on PubMed. They discuss potential risks too.
       
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    11. paul mclean

      paul mclean Member

      Tinnitus Since:
      2018
      Cause of Tinnitus:
      falling asleep with headphones in on loud
      Will report back here soon, it has almost arrived at my place.

      I've read the study you're referring to
      .
      Here is another study using Bisphosphonates (Risedronate) and a TRKB agonist (7,8,DHF).

      They use Risedronate as a delivery method to get the TRKB agonist to the cochlear which increases NT3 and BDNF to repair the synapses. Pretty cool stuff.

      I went with Zoledronic acid though due to its 100% bioavailability due to the IV and not oral. Risedronate's bioavailability is poor and can cause real bad stomach and esophagus issues. I already have bad acid reflux so this was a no go for me.

      Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss

      The main things I've taken from the research I've done is that they do reach the cochlear and repair synapses (in mice) but they are pretty serious drugs with potential for awful side effects.

      I actually have some 7,8-DHF too as I am into my nootropics so I'll be taking a large dose of that along with my Zoledronic acid IV.

      I'd say I'll be doing this within 2-4 weeks. Just waiting for a little break from work. Zoledronic acid has an acute phrase reaction period which lasts around 3 days (APR) where people get flu like symptoms and bad body pain, bone aches and diarrhoea.
      Now this is at the full doses (4 or 5 mg) and I'll be doing 0.5 mg . So pretty much 1/10 of the dose for osteoporosis. So I think it'll minimize the chances for the unwanted adverse reactions but safe to just take a couple days off and rest anyway.

      I'm getting excited but a little nervous too.
       
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    12. Hottopic29

      Hottopic29 Member Benefactor

      Location:
      Niagara falls
      Tinnitus Since:
      11/2013
      Cause of Tinnitus:
      Zithromycin acoustic trauma 2022
      I read before that osteoporosis affects the little bones in the ear. Will Bisphosphonate only help people who got tinnitus from osteoporosis?
       
    13. paul mclean

      paul mclean Member

      Tinnitus Since:
      2018
      Cause of Tinnitus:
      falling asleep with headphones in on loud
      It depends. If your tinnitus is from cochlear synaptopathy and the Bisphosphonates regenerate the IHC afferent synapses then it'll affect your tinnitus whether you have osteoporosis or not.

      Also my Zoledronic acid arrived today. The preparation begins, I'll need a period of 3-4 days off work so I'll figure that out in the next 4 weeks and report back.
       
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    14. Ela Stefan

      Ela Stefan Member

      Tinnitus Since:
      11/2018
      Cause of Tinnitus:
      Ear Infection
      How can you get that drug? How could you convince a doctor to prescribe the treatment to you since it is not a conventional one?
       
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    15. paul mclean

      paul mclean Member

      Tinnitus Since:
      2018
      Cause of Tinnitus:
      falling asleep with headphones in on loud
      It's actually very easy.

      AllDayChemist or IndiaMART. No prescription required.
       
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    16. Ela Stefan

      Ela Stefan Member

      Tinnitus Since:
      11/2018
      Cause of Tinnitus:
      Ear Infection
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    17. Franci003

      Franci003 Member

      Tinnitus Since:
      12/2021
      Cause of Tinnitus:
      Acoustic Trauma
      Keep us updated, I hope it works! Would it also be effective for IHC and OHC damage?
       
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    18. paul mclean

      paul mclean Member

      Tinnitus Since:
      2018
      Cause of Tinnitus:
      falling asleep with headphones in on loud
      I've been real busy recently but I've pivoted slightly in my approach.

      I have the Zoledronate ready to go but I've actually found a biotech company that can custom synthesise Risedronate-7,8,DHF conjugate for me which I can take in a pill/capsule form.

      I'd much rather take a pill that works than the intravenous injection. Risedronate also has significantly less side effects than Zoledronate. Zoledronate stays in your bones for up to 10 years. Risedronate for 6-12 months.

      Here is the study of the Risedronate-7,8,DHF conjugate. The Risedronate is pretty much a delivery system for the DHF to get to the cochlear and repair the synapses:

      Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss

      So the plan is to order the Risedronate-7,8,DHF conjugate and try that first. If that fails/doesn't work, then I will resort to the Zoledronate. The whole process may take me another month or two but I'll definitely post updates.
       
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    19. paul mclean

      paul mclean Member

      Tinnitus Since:
      2018
      Cause of Tinnitus:
      falling asleep with headphones in on loud
      Someone can correct me if I'm wrong but I'm fairly certain cochlear synaptopathy is only damage to the synapses of the inner hair cells.

      So I'm uncertain what effects the bisphosphonates would have on outer hair cells.

      Read through this study if you have the time, you may find some more information:

      Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate
       
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