TNF Alpha and Brain Inflammation

[DebInAustralia]

Hello,

Humour me. I was watching a program on tv tonight that featured the use of a drug that has traditionally been used to treat rheumatoid arthritis (an immune modulator). The drug in question; Enbrel, is now being applied to the treatment of stroke in the states, and trials are commencing in Australia next year. Researchers interviewed in the program stated that they felt Enbrel is an exciting drug with potential for more widespread use in neurodegenerative conditions. Whilst tinnitus wasn't specifically mentioned, I cant help but wonder if addressing brain inflammation by reducing TNF alpha (as in the case of Enbrel) would be helpful? Are there any threads on this forum on this topic? Has there ever been a link made between raised TNF and tinnitus? Pardon my ignorance.

Dr google revealed a bunch of info on brain inflammation. I found some possible hypotheses for the generation of brain inflammation ..

. an increase in TNF alpha causes an increase in AMPAR (a neuronal receptor for glutamate) which leads to an increase in glutamic receptors, causing an increased sensitivity in surrounding tissue, and hence increased neuronal excitability.

. TNF alpha mediated inflammation leads to changes in the properties of helper brain cells (astrocytes) which regulate glutamic acid, leading to a loss of glutamic acid regulation, causing an oversensitisation of neurons.

. Other theories include: the suppression of the production of new hippocampus neurons (neurogenesis), and decrease in the microglial cell's normal ability to repair and maintain neuronal synapses.

So, where am going with all of this?

1. could immune modulators like Enbrel/other have a role to play in treating tinnitus assuming brain inflammation is involved?

2. what are the ways in which TNF alpha can be reduced?

3. Can changes in neurons (ie increased sensitivity to neurotransmitters) be reversed? Can synapses be repaired?

any thoughts?

 

[Stink]

Hello,

Humour me. I was watching a program on tv tonight that featured the use of a drug that has traditionally been used to treat rheumatoid arthritis (an immune modulator). The drug in question; Enbrel, is now being applied to the treatment of stroke in the states, and trials are commencing in Australia next year. Researchers interviewed in the program stated that they felt Enbrel is an exciting drug with potential for more widespread use in neurodegenerative conditions. Whilst tinnitus wasn't specifically mentioned, I cant help but wonder if addressing brain inflammation by reducing TNF alpha (as in the case of Enbrel) would be helpful? Are there any threads on this forum on this topic? Has there ever been a link made between raised TNF and tinnitus? Pardon my ignorance.

Dr google revealed a bunch of info on brain inflammation. I found some possible hypotheses for the generation of brain inflammation ..

. an increase in TNF alpha causes an increase in AMPAR (a neuronal receptor for glutamate) which leads to an increase in glutamic receptors, causing an increased sensitivity in surrounding tissue, and hence increased neuronal excitability.

. TNF alpha mediated inflammation leads to changes in the properties of helper brain cells (astrocytes) which regulate glutamic acid, leading to a loss of glutamic acid regulation, causing an oversensitisation of neurons.

. Other theories include: the suppression of the production of new hippocampus neurons (neurogenesis), and decrease in the microglial cell's normal ability to repair and maintain neuronal synapses.

So, where am going with all of this?

1. could immune modulators like Enbrel/other have a role to play in treating tinnitus assuming brain inflammation is involved?

2. what are the ways in which TNF alpha can be reduced?

3. Can changes in neurons (ie increased sensitivity to neurotransmitters) be reversed? Can synapses be repaired?

any thoughts?

did you research this more? are you onto something here?

 

[DebInAustralia]

No, I haven't researched it more yet......WOrk has kinda taken over my time again but I will...

 

[Autumnly]

Dramatic headline incoming by Mail Online:

"Drug to reduce brain inflammation CURED tinnitus in mice - paving the way towards a pill for humans"

• The condition was stopped in mice by blocking a protein that fuels brain inflammation
• The Arizona team are hopeful it will lead to a gene therapy to combat tinnitus and other hearing loss disorders
• More information: Wang W, Zhang LS, Zinsmaier AK, Patterson G, Leptich EJ, Shoemaker SL, et al. (2019) Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models. PLoS Biol 17(6): e3000307. doi.org/10.1371/journal.pbio.3000307

A pill to cure the misery of tinnitus could be on the horizon following a breakthrough by scientists. The debilitating condition was stopped in mice by blocking a protein that fuels brain inflammation. The US team are hopeful it will lead to a gene therapy to combat ringing in the ears and other hearing loss disorders.

The study, published in the journal PLOS Biology, suggests it is caused by a molecule called TNF-A (tumor necrosis factor alpha) that disrupts communication between neurons. Blocking it pharmacologically also prevented tinnitus in lab rodents that developed the condition after being exposed to loud noise for two hours. The findings suggest neuro-inflammation may be a therapeutic target for treating tinnitus and other hearing problems, said the researchers.

Study co-author Dr Shaowen Bao said: 'Genetic knock out of TNF-A or pharmacologically blocking its expression prevented neuro-inflammation and ameliorated the behavior associated with tinnitus in mice with noise induced hearing loss.' Analysis showed inflammation in a sound-processing region of the brain controls ringing in the ears in the affected mice that have noise-induced hearing loss.

Analysis showed inflammation in a sound-processing region of the brain controls ringing in the ears in the affected mice that have noise-induced hearing loss. Dr Bao, a neuroscientist at the University of Arizona, said: 'Hearing loss is a widespread condition that affects approximately 500 million individuals, and is a major risk factor for tinnitus - the perception of noise or ringing in the ears.'

Recent research suggests hearing loss causes inflammation - the immune system's response to injury and infection - in the auditory pathway. But its contribution to hearing loss-related conditions such as tinnitus is still poorly understood. Dr Bao and colleagues examined neuro-inflammation - inflammation that affects the nervous system - in the auditory cortex of the brain following noise-induced hearing loss, and its role in tinnitus, in the rodent models.

He said: 'The results indicate noise-induced hearing loss is associated with elevated levels of molecules called proinflammatory cytokines and the activation of non-neuronal cells called microglia - two defining features of neuroinflammatory responses - in the primary auditory cortex.'

Dr Bao added: 'These results implicate neuro-inflammation as a therapeutic target for treating tinnitus and other hearing loss related disorders.' But he pointed out that although the therapy was successful in the animals, its potential adverse affects need to be thoroughly investigated before any human trials.

 

[GSC]

:O

 

[ChrisBoyMonkey]

Dramatic headline incoming by Mail Online:

"Drug to reduce brain inflammation CURED tinnitus in mice - paving the way towards a pill for humans"

• The condition was stopped in mice by blocking a protein that fuels brain inflammation
• The Arizona team are hopeful it will lead to a gene therapy to combat tinnitus and other hearing loss disorders
• More information: Wang W, Zhang LS, Zinsmaier AK, Patterson G, Leptich EJ, Shoemaker SL, et al. (2019) Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models. PLoS Biol 17(6): e3000307. doi.org/10.1371/journal.pbio.3000307

A pill to cure the misery of tinnitus could be on the horizon following a breakthrough by scientists. The debilitating condition was stopped in mice by blocking a protein that fuels brain inflammation. The US team are hopeful it will lead to a gene therapy to combat ringing in the ears and other hearing loss disorders.

The study, published in the journal PLOS Biology, suggests it is caused by a molecule called TNF-A (tumor necrosis factor alpha) that disrupts communication between neurons. Blocking it pharmacologically also prevented tinnitus in lab rodents that developed the condition after being exposed to loud noise for two hours. The findings suggest neuro-inflammation may be a therapeutic target for treating tinnitus and other hearing problems, said the researchers.

Study co-author Dr Shaowen Bao said: 'Genetic knock out of TNF-A or pharmacologically blocking its expression prevented neuro-inflammation and ameliorated the behavior associated with tinnitus in mice with noise induced hearing loss.' Analysis showed inflammation in a sound-processing region of the brain controls ringing in the ears in the affected mice that have noise-induced hearing loss.

Analysis showed inflammation in a sound-processing region of the brain controls ringing in the ears in the affected mice that have noise-induced hearing loss. Dr Bao, a neuroscientist at the University of Arizona, said: 'Hearing loss is a widespread condition that affects approximately 500 million individuals, and is a major risk factor for tinnitus - the perception of noise or ringing in the ears.'

Recent research suggests hearing loss causes inflammation - the immune system's response to injury and infection - in the auditory pathway. But its contribution to hearing loss-related conditions such as tinnitus is still poorly understood. Dr Bao and colleagues examined neuro-inflammation - inflammation that affects the nervous system - in the auditory cortex of the brain following noise-induced hearing loss, and its role in tinnitus, in the rodent models.

He said: 'The results indicate noise-induced hearing loss is associated with elevated levels of molecules called proinflammatory cytokines and the activation of non-neuronal cells called microglia - two defining features of neuroinflammatory responses - in the primary auditory cortex.'

Dr Bao added: 'These results implicate neuro-inflammation as a therapeutic target for treating tinnitus and other hearing loss related disorders.' But he pointed out that although the therapy was successful in the animals, its potential adverse affects need to be thoroughly investigated before any human trials.

Awesome find! Even if this drug were to have adverse effects, there could always be an attempt to redesign just like Dr. Tzounopoulos is redesigning trobalt to LR-81.

 

[Mathieulh]

Causing brain inflammation is definitely not benign and could lead to serious, severe, cognitive impairments on the long term, such as it has been demonstrated on multiple occasions by pathologies causing similar effects, this leads me to be rather skeptical about this drug, but if it does work and the side effects end up minimal, it's worth looking into and would provide great relief to a lot of sufferers.

 

[RichardGuy]

@Autumnly so what happens now? Seems like they haven't even started a trial yet.

 

[Lane]

DMSO is very effective at rapidly reducing brain inflammation, and according to my understanding, has become the drug of choice in ERs to immediately administer for closed head injuries. The drugs they used previously apparently didn't even come close to matching the effectiveness of DMSO, which is being credited with saving many lives.

 

[Piney]

I think there's something here. How can you get T from hearing loss, neck problems, sporadic with good hearing, drugs, and I'm sure other methods. We know it's in the brain somewhere, I hope the Univ of Arizona is working quick on this. Maybe these electrical devised are doing this on a small scale, like a tens unit internally zapping the inflammation down. But maybe it only works to a degree. This site should be hounding these Arizona professors as much as Neuromod. Maybe I'll start.

 

[ToreNorway]

Dramatic headline incoming by Mail Online:

"Drug to reduce brain inflammation CURED tinnitus in mice - paving the way towards a pill for humans"

• The condition was stopped in mice by blocking a protein that fuels brain inflammation
• The Arizona team are hopeful it will lead to a gene therapy to combat tinnitus and other hearing loss disorders
• More information: Wang W, Zhang LS, Zinsmaier AK, Patterson G, Leptich EJ, Shoemaker SL, et al. (2019) Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models. PLoS Biol 17(6): e3000307. doi.org/10.1371/journal.pbio.3000307

A pill to cure the misery of tinnitus could be on the horizon following a breakthrough by scientists. The debilitating condition was stopped in mice by blocking a protein that fuels brain inflammation. The US team are hopeful it will lead to a gene therapy to combat ringing in the ears and other hearing loss disorders.

The study, published in the journal PLOS Biology, suggests it is caused by a molecule called TNF-A (tumor necrosis factor alpha) that disrupts communication between neurons. Blocking it pharmacologically also prevented tinnitus in lab rodents that developed the condition after being exposed to loud noise for two hours. The findings suggest neuro-inflammation may be a therapeutic target for treating tinnitus and other hearing problems, said the researchers.

Study co-author Dr Shaowen Bao said: 'Genetic knock out of TNF-A or pharmacologically blocking its expression prevented neuro-inflammation and ameliorated the behavior associated with tinnitus in mice with noise induced hearing loss.' Analysis showed inflammation in a sound-processing region of the brain controls ringing in the ears in the affected mice that have noise-induced hearing loss.

Analysis showed inflammation in a sound-processing region of the brain controls ringing in the ears in the affected mice that have noise-induced hearing loss. Dr Bao, a neuroscientist at the University of Arizona, said: 'Hearing loss is a widespread condition that affects approximately 500 million individuals, and is a major risk factor for tinnitus - the perception of noise or ringing in the ears.'

Recent research suggests hearing loss causes inflammation - the immune system's response to injury and infection - in the auditory pathway. But its contribution to hearing loss-related conditions such as tinnitus is still poorly understood. Dr Bao and colleagues examined neuro-inflammation - inflammation that affects the nervous system - in the auditory cortex of the brain following noise-induced hearing loss, and its role in tinnitus, in the rodent models.

He said: 'The results indicate noise-induced hearing loss is associated with elevated levels of molecules called proinflammatory cytokines and the activation of non-neuronal cells called microglia - two defining features of neuroinflammatory responses - in the primary auditory cortex.'

Dr Bao added: 'These results implicate neuro-inflammation as a therapeutic target for treating tinnitus and other hearing loss related disorders.' But he pointed out that although the therapy was successful in the animals, its potential adverse affects need to be thoroughly investigated before any human trials.

Are there any news on this. Surely 2020 isn't all bad news, so there is bound to be something?

 

[FGG]

This part of this study was always interesting to me:

"Therefore, it is possible that the tinnitus induced by cortical TNF-α infusion was weaker than that induced by noise exposure because of the lack of subcortical involvement."

Basically, you got a weaker tinnitus (though they still got tinnitus) from directly infusing TNF alpha into the brain if there is no hearing loss than from noise and resulting hearing damage. I.e. Subcortical inflammation (cochlear damage and resultant fusiform cell activation in the cochlear nucleus) results in a worse tinnitus than directly causing brain inflammation through TNF alpha injection into the auditory cortex. Which again, suggest the real underlying problem is not the brain, the brain is just reacting to the damage.

Frustratingly the lay reporting on this suggests the opposite. Here is the full study: https://scholar.google.com/scholar?q=bao+tinnitus+tnf+alpha&hl=en&as_sdt=0&as_vis=1&oi=scholart#d=gs_qabs&u=#p=-Ve8KEHLjg8J

 

[Christiaan]

Clinical trial: TNF-α Treatment of Blast-Induced Tinnitus

Brief Summary:
This study evaluates the therapeutic effects of Etanercept (Enbrel) on the treatment of blast/noise induced tinnitus in adults. Half of the participants will receive 2 x 25mg Entanercept injections, and the other half will receive placebo injections.

Estimated Study Start Date: August 2020
Estimated Primary Completion Date: September 2022

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

 

[spedgas]

Clinical trial: TNF-α Treatment of Blast-Induced Tinnitus

Brief Summary:
This study evaluates the therapeutic effects of Etanercept (Enbrel) on the treatment of blast/noise induced tinnitus in adults. Half of the participants will receive 2 x 25mg Entanercept injections, and the other half will receive placebo injections.

Estimated Study Start Date: August 2020
Estimated Primary Completion Date: September 2022

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

Hmmm... I work at one of the facilities performing the study. I'm a nurse and have patients on similar medications (Humira and Remicade). I might have to try and participate in this.

 

[Ozwel]

Hi, can anyone see me? I'm posting but my post from yesterday has disappeared.

Humira, Remicade are the most common anti TNF alpha, but there are plenty of others. Patients have to try many of the before finding the right one for them. When you're done with anti TNF and none of them have worked on you, you have to try anti IL17 and anti IL23.

The best thing you can do is to find the cytokines in excess in your blood. Then it's easier to find the right biomed for you.

See my thread for more info: https://www.tinnitustalk.com/thread...ition-new-treatment-paths-would-appear.42222/

 

[Christiaan]

Hmmm... I work at one of the facilities performing the study. I'm a nurse and have patients on similar medications (Humira and Remicade). I might have to try and participate in this.

Great news that you're living next to one of the research facilities. It's incredible how much research on tinnitus is going on in the US. If you do not have do sign an NDA, could you inform us when you're part of the study?

 

[Christiaan]

Here are other locations in case people are interested:

Locations

United States, Arizona

University of Arizona-AHSC Bldg

Tucson, Arizona, United States, 85721

Principal Investigator: Shaowen Bao, Ph.D.

Sub-Investigator: Faydyeh Barakat


United States, Florida

University of Miami

Coral Gables, Florida, United States, 33124

Principal Investigator: Michael Hoffer, MD


United States, Illinois

University of Illinois at Urbana-Champaign

Champaign, Illinois, United States, 61820

Principal Investigator: Fatima Husain, Ph.D.


United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

Principal Investigator: Richard Tyler, Ph.D./CCC-A


United States, Michigan

John D. Dingell VA Medical Center

Detroit, Michigan, United States, 48201

Principal Investigator: Michael Carron, MD

Wayne State University

Detroit, Michigan, United States, 48201

Principal Investigator: Jinsheng Zhang, Ph.D.

Michigan Ear Institute

Farmington Hills, Michigan, United States, 48334

Principal Investigator: Robert Hong, MD/Ph.D.

Sub-Investigator: Dennis Bojrab


United States, Oregon

VA Portland Health Care System

Portland, Oregon, United States, 97239

Principal Investigator: Robert Folmer, Ph.D

Sub-Investigator: Sara Theodoroff, Ph.D./CCC-A


United States, Texas

Brooke Army Medical Center

Fort Sam Houston, Texas, United States, 78234

Principal Investigator: Brent J Wilkerson, MD

 

[Christiaan]

Based on findings, the researchers think TNF-a blockers like Etanercept may help chronic tinnitus. There's also clinical evidence that closely related medication (Misoprostol) significantly reduces severity of tinnitus and loudness. More can be found in the clinical trial plan: https://clinicaltrials.gov/ProvidedDocs/48/NCT04066348/Prot_000.pdf

 

[Ozwel]

Well I'm starting anti TNF alpha aka Etanercept very soon. My doctor wants me to try Humira (a competitor) before maybe but I may suggest the one I wish to try first.

Also, Artemisia Annua (a plant) is known for its anti TNF alpha properties. You may want to try. It takes up to 6 weeks before the immune system is impacted (T cells) and you feel the first signs of improvements.

For more info about Artemisia and its anti TNF alpha effect: https://www.sciencedirect.com/science/article/abs/pii/S0944711309002682

 

[Christiaan]

Well I'm starting anti TNF alpha aka Etanercept very soon. My doctor wants me to try Humira (a competitor) before maybe but I may suggest the one I wish to try first.

Also, Artemisia Annua (a plant) is known for its anti TNF alpha properties. You may want to try. It takes up to 6 weeks before the immune system is impacted (T cells) and you feel the first signs of improvements.

For more info about Artemisia and its anti TNF alpha effect: https://www.sciencedirect.com/science/article/abs/pii/S0944711309002682

Thanks for the info @Ozwel. I will give it some thought about whether or not I will experiment with Artemisia Annua.

So are you going for the trials or are you going to use Etanercept on prescription?

 

[Ozwel]

I'm going for Etanercept on prescription. It may be Humira instead... it will depend on my doctor's advice but in the end it shares the same goal.

It's pending my blood test results, it has to be clean before starting an immunosuppressive drug.

 

[AnxiouslyWaiting]

I'm going for Etanercept on prescription. It may be Humira instead... it will depend on my doctor's advice but in the end it shares the same goal.

It's pending my blood test results, it has to be clean before starting an immunosuppressive drug.

Please share how it goes for you. Good luck!

 

[DebInAustralia]

Well I'm starting anti TNF alpha aka Etanercept very soon. My doctor wants me to try Humira (a competitor) before maybe but I may suggest the one I wish to try first.

Also, Artemisia Annua (a plant) is known for its anti TNF alpha properties. You may want to try. It takes up to 6 weeks before the immune system is impacted (T cells) and you feel the first signs of improvements.

For more info about Artemisia and its anti TNF alpha effect: https://www.sciencedirect.com/science/article/abs/pii/S0944711309002682

I was on Artemisia for a short time for Babesia, and I had to stop taking it because it seemed to make my tinnitus worse.

 

[Zugzug]

I'm going for Etanercept on prescription. It may be Humira instead... it will depend on my doctor's advice but in the end it shares the same goal.

It's pending my blood test results, it has to be clean before starting an immunosuppressive drug.

Hi @Ozwel. I am sorry to hear that you are struggling and needing to resort to TNF-alpha inhibitors. If you don't mind I had a few questions for you.

My doctor is tentatively (unofficially) diagnosing me with autoimmune inner ear disease based on responsiveness to steroids. I asked him about TNF-alpha inhibitors like Etanercept and he said that they are extremely expensive and unlikely to be covered by insurance.

Do you have any experiences with this? I would love to try this, especially if other things don't work.

 

[asey20]

My doctor is tentatively (unofficially) diagnosing me with autoimmune inner ear disease based on responsiveness to steroids.

What kind of response was it, a negative or positive response to the steroids?

 

[DebInAustralia]

Hi @Ozwel. I am sorry to hear that you are struggling and needing to resort to TNF-alpha inhibitors. If you don't mind I had a few questions for you.

My doctor is tentatively (unofficially) diagnosing me with autoimmune inner ear disease based on responsiveness to steroids. I asked him about TNF-alpha inhibitors like Etanercept and he said that they are extremely expensive and unlikely to be covered by insurance.

Do you have any experiences with this? I would love to try this, especially if other things don't work.

Why not try low dose naltrexone?
I think it inhibits TNF alpha also.

 

[Christiaan]

@Ozwel has inspired me to declare war on tinnitus. I've decided to start Etanercept on prescription in a month or so. I will combine this with an anti-inflammatory gluten free, organic vegan diet + natural TNF inhibitors (curcumin, spirulina, etc.) + intermittent fasting. Will get in touch with y'all when I get more info from my doctor.

 

[Lane]

My doctor is tentatively (unofficially) diagnosing me with autoimmune inner ear disease based on responsiveness to steroids.

@Zugzug -- You may be interested in the following post I made recently:

Prednisone for Hyperacusis: Any Experiences? Natural Alternatives?

 

[Zugzug]

@Zugzug -- You may be interested in the following post I made recently:

Prednisone for Hyperacusis: Any Experiences? Natural Alternatives?

Thanks. I actually posted in there a while back. I have recently had more success with prednisone after going to a higher dose and for more time.

 

[Zugzug]

@Ozwel has inspired me to declare war on tinnitus. I've decided to start Etanercept on prescription in a month or so. I will combine this with an anti-inflammatory gluten free, organic vegan diet + natural TNF inhibitors (curcumin, spirulina, etc.) + intermittent fasting. Will get in touch with y'all when I get more info from my doctor.

Please keep us in the loop. I had the same thought process as you, that I'll just ask my doctor for Etanercept. Then I had a discussion with him and found out that it's insanely expensive.

By the way, I also take Curcumin. I am interested in intermittent fasting.