Neuroinflammation Mediates Noise-Induced Synaptic Imbalance and Tinnitus in Rodent Models

Thanks for this update. Glad to see that. Frustrating that the study will take 2-3 years to complete, considering it's a drug already on the market.

 

It's strange, in that clinical trial, there are two opposite histories of tinnitus :

"Tinnitus history: Onset associated with blast- and/or noise exposure. Subjects will have either recent blast or noise exposure, defined as exposure less than six months ago at time of enrollment, or historical exposure, defined as exposure 6 months or longer ago at time of enrollment."

 

Perhaps it might be worth trying to get out hands on Enbrel ourselves? If it's possible...

 

I had an appointment with my neurologist yesterday and asked him about Enbrel as a potential treatment for tinnitus. He thought it sounded promising, but told me I’d need to get a rheumatologist to prescribe and manage it for me, and I’d need a diagnosis (rheumatoid arthritis would be the most common) that clearly supported it or insurance wouldn’t pay. Apparently this class of drugs is one of the most expensive in the world - often $10k per month in the US. Also noted that side effects on this one can be rough/dangerous, and it’s on the FDA Blackbox list as a result.

@Frédéric I agree the study has conflicting parameters about blast and noise, and duration.

 

Interesting. There was in 2001 already a trial which tested Etanercept as possible hearing / tinnitus therapy. And showed promising results.

https://www.ncbi.nlm.nih.gov/pubmed/11568668

18 years for a follow up trial. Seems kind of long.

 

Just to add: They did another trial in 2005

https://www.ncbi.nlm.nih.gov/pubmed/15934127

which revealed that Etanercept has not the efficacy as initially expected. But I really really hope that Dr. Bao has brought some new idea to the table which was not already considered a decade ago.

 

I’ve read about TNF-Alpha being responsible for the generation of tinnitus before, but using medications to suppress its expression is news to me. Does anyone have any idea as to what is the medication these researchers are using?

Here’s the paper, but it doesn’t mention what they used. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000307

Here’s a list of them, apparently? Anyone tried any of these?

https://www.drugs.com/drug-class/tnf-alfa-inhibitors.html

edit: I actually have ulcerative colitis so I could realistically be put on one of these drugs. I’m going to ask my GP about it.

 

I have UC and am going to the quickest doctor available to give me remicade, simponi or humira.

ACTUAL PERTINENT QUESTION: if tinnitus is partially a product of auditory cortex inflammation, would removing this inflammation with a powerful TNF-A inhibitor cause the tinnitus to cease regardless of whether the case is chronic or acute? Or is the idea that chronic inflammation has already wrought all the havoc it needed to on the auditory system?

 

I’m confused, does the inflammation persist for life or go away on its own? What level of exposure is needed to cause the inflammation? If my hearing is still normal, am I probably ok? I know my middle/inner ear is swollen but I’m confused about what the brain mechanism is.

 

I missed where the auditory cortex is inflammed. Can someone link me the pertinent passage?

 

Although recent studies indicate that hearing loss causes neuroinflammation in the auditory pathway, the mechanisms underlying hearing loss–related pathologies are still poorly understood. We examined neuroinflammation in the auditory cortex following noise-induced hearing loss (NIHL) and its role in tinnitus in rodent models. Our results indicate that NIHL is associated with elevated expression of proinflammatory cytokines and microglial activation—two defining features of neuroinflammatory responses—in the primary auditory cortex (AI).

 

Nevermind, found the original paper:

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000307

It's really interesting because they suggest that microglial activation is the source of the inflammation and that GABA/Glutamate imbalance allows it to persist (i wonder if this is at least partly why GABA agonist drugs can hinder neuroplasticity).

What's also interesting is that injecting TNF alpha directly into the Auditory Cortex causes a much more mild tinnitus than noise exposure and the authors basically admitted that the subcortical inflammation (ear through brainstem) which also involved TNF alpha was much more of a significant factor. This actually means to me that tinnitus is not "in the brain" (unless brainstem is included in that statement) but microglial activation can exacerbate it and Neuro transmitter normalization would be part of the plasticity puzzle once underlying causes are addressed.

 

I think here is a good summary of the paper from Bao:

https://uanews.arizona.edu/story/brain-inflammation-identified-potential-target-treat-tinnitus

They say inflammation may be the root cause of T. But it is not that easy to just take a good TNF-a inhibitor and then we are T free. Then we would have heard of all the rheumatoid atritis patients who are T free after taking these meds. I hope they do another trial with some animals who's auditory system is more human like. Since healing T in rats many drugs have done and unfortunately never did these results translate to humans.

 

Since the inflammation is in response to damage to the nerves in the ears, would correcting this damage eliminate the inflammation? Or would it just keep going as a continuous process?

 

If I'm reading it right, the full paper seems to imply that, by itself, inflammation in the auditory center only produces a more mild tinnitus and it also says the GABA/Glutamate imbalance perpetuates the imbalance (in the brain, but it also does this in the cochlea) so my guess is as long as you aren't messing with your receptors too much (I'm a little worried about long term benzos here but maybe I'm off base), neuro plasticity should happen and your receptors normalize and tinnitus should resolve.

 

I've done a cytokine panel in Australia.

It demonstrated my TNF-a is elevated.

 

I hope that's the road I'm on. Recently I have started taking a small amount of clonazepam (thanks family members) when I start spiking really bad and it cuts it by like 50%, and fullness also goes away. I really feel like perpetual inflammation is the root cause of my tinnitus which was triggered by a night of drinking too much at high altitude (extreme vasodilation?) and who knows what damage that did, but not enough to affect my hearing and the tinnitus SHOULD be resolving. It's like it tries to but then comes back.

 

The side effects of the TNF inhibition will not be worth it for me.

https://en.wikipedia.org/wiki/TNF_inhibitor

I wonder how the elevated TNF levels fits with the idea that bimodal simulation can be a cure. Does bimodal stimulation reduce TNF levels or do they just reduce the effects of high TNF levels?

 

Are you speculating or have your read that bimodal stimulation impacts on TNF-a?

 

Speculating. They seem like two contradictory ideas. But it might be that bimodal stuff just inhibits neuronal activity in other way. But that would mean that one needs to stay with bimodal for the rest of the life because otherwise elevated TNF levels would bring tinnitus back.

 

Any updates?

 

I did a cytokine panel that is able to measure serum TNF.

 

Not sure if this has been posted before, but there is currently a TNF-alpha trial in phase 2 on blast induced tinnitus ongoing. Primary end date sept 2022.

https://clinicaltrials.gov/ct2/show/NCT04066348

Seems that this etanersept injectable biologic has been on the market for 20 years already. It’s passed human safety trials, with main side effects being a decreased ability to fight infection as you’re essentially dampening your immune system.

 

Have you tried low dose naltrexone, in an attempt to modulate TNF-alpha?

I've always wondered why my tinnitus fluctuates so much with stable hearing loss?

Is there such a thing as cochlear inflammation? Pardon my ignorance.

 

Did you manage to get a hold of it?

 

I know there are older threads on here regarding Resveratrol.

Just wondered if anyone has thought to try it as it is meant to be capable of deactivating microglial cells that turn on TNF; leading to neuroinflammation.

 

If this poster is still about, which TNF-alpha inhibitor were you taking if you don't mind me asking?

 

Baclofen.

 

TNF-α Treatment of Blast-Induced Tinnitus

The related study is recruiting as per yesterday for noise-induced tinnitus.

It is changed from blast-induced tinnitus to noise-induced tinnitus.

Etanercept is the medicine. Phase 2 study with repurposing of drug - so no Phase 3 required.

Another one ongoing!

 

I wonder do they have some anecdotal evidence of Enbrel providing a benefit - Enbrel is widely used by people with chronic rheumatoid arthritis and other immune related inflammatory diseases. Some portion of them must have tinnitus.

I took Enbrel for 10 years, before going into remission and haven't needed it for almost 5 years now. This was pre-severe tinnitus. In fact, I still have a couple months supply in the fridge but it's past its 'use by' date by a couple of years so not sure the wisdom of trying it now!