Blocking the endotoxin receptor (TLR4) may prevent / treat hearing loss

[haidut]

I did a post a few months ago on the connection between tinnitus and serotonin - i.e. using anti-serotonin drugs may treat tinnitus. Since tinnitus is almost always a precursor state to hearing loss (and eventually deafness), the two conditions obviously go hand-in-hand and are likely caused by the same agent (e.g. serotonin). Since more than 90% of serotonin is synthesized in the GI tract, these hearing pathologies suggest that a digestive process is driving the increase in serotonin synthesis and in most of the cases this process is increased endotoxin (LPS) release and absorption into the bloodstream. Endotoxin (LPS) triggers serotonin synthesis/release mostly through activation of the TLR4 receptor. This line of reasoning suggests that of serotonin is the cause of tinnitus and hearing loss, and its synthesis is driven mostly by endotoxin (LPS) through activation of TLR4 then blocking TLR4 should have therapeutic effects for these conditions. And that is exactly what the study below found - i.e. administration of a TLR4 antagonist prevented damage to the hearing apparatus triggered by a chemotherapy drug with known serotonergic properties.

https://www.embopress.org/doi/full/10.15252/embr.202051280
Receptor inhibition may prevent hearing loss due to chemotherapy drug cisplatin: Study

"...The cells affected by TLR4's signals are located within the cochlea of the ear, where they play a crucial role in hearing, translating vibrations in the ear info electrical impulses..."These cells don't renew. You really only get one shot and if they're gone, you're in trouble. The hearing loss is permanent," said Bhavsar. The only way to prevent the damage is to stop the signals TLR4 produces that lead to the accumulation of cisplatin. To confirm the efficacy of inhibiting the TLR4 receptor, Bhavsar and his team looked at zebrafish models, with the help of Ted Allison, an associate professor in the Department of Biological Sciences and member of the U of A's Neuroscience and Mental Health Institute. They examined neuromasts, which are sensory cells within zebrafish that behave similar to the human hair cells typically damaged by cisplatin. Bhavsar was able to prove that inhibiting TLR4 led to inhibition of the damage on the sensory cells."

 

[equipoise]

My mother is deaf on one ear and the other is slowly going away. What's a good treatment? @haidut

 

[dabdabdab]

then can you explain how quinine which reduces endotoxin can cause deafness and blindness? is there any correlation?

 

[dabdabdab]

@haidut

 

[TobyBjorn]

Ibudilast has been very helpful for me with TLR4 mediated problems.

 

[Sefton10]

My mother is deaf on one ear and the other is slowly going away. What's a good treatment? @haidut

Would love a response to this too

 

[Hans]

Emodin is a great TLR4 antagonist. Lapodin is great for the gut. It remodulates the gut in a positive way, inhibits leaky gut and also antagonizes thr TLR4 receptor. And these are just a few of its benefits.

 

[Mito]

Lapodin is great for the gut.

Do you think topical Lapodin is as effective for the gut as taking it orally?

 

[Hans]

Do you think topical Lapodin is as effective for the gut as taking it orally?

Not sure. I've applied it topical before, but it just sits there on the skin for hours. I prefer oral. Sublingual also works if you can tolerate the burn.

 

[Judd Crane]

If serotonin causes tinnitus, how come NMDA-antagonists lowers tinnitus? Is it because they decrease serotonin? Or is glutamate the direct cause of tinnitus and serotonin causes tinnitus by elevating glutamate?

 

[Davinci]

If serotonin causes tinnitus, how come NMDA-antagonists lowers tinnitus? Is it because they decrease serotonin? Or is glutamate the direct cause of tinnitus and serotonin causes tinnitus by elevating glutamate?

NMDA-antagonists can lower tinnitus? Do you know how that mechanism works?

 

[SaltiestSardine]

NMDA-antagonists can lower tinnitus? Do you know how that mechanism works?

He just said. They either compete for absorption with the same receptors as NMDA like magnesium, or they facilitate the breakdown of glutamate like NAC, or inhibit NMDA receptors entirely like Agmatine. Excitotoxicity is one of many things that can kill off the inner ear hair cells and glutamate is a driver of that. It also messes around with lymph fluid in the inner canal which from some studies seem to apply a dysregulation in the mineral salts in that have a role to play in tinnitus, NIHL, and AIHL. It doesn't have anything to do with serotonin, but i know some of you wanna die on that hill.

Agmatine quite consistently lessens my tinnitus considerably whenever i take it. Anything dopaminergic increases my tinnitus tenfold as dopamine and glutamate are very inter-connected. There's no room for debate here for me

 

[Judd Crane]

He just said. They either compete for absorption with the same receptors as NMDA like magnesium, or they facilitate the breakdown of glutamate like NAC, or inhibit NMDA receptors entirely like Agmatine. Excitotoxicity is one of many things that can kill off the inner ear hair cells and glutamate is a driver of that. It also messes around with lymph fluid in the inner canal which from some studies seem to apply a dysregulation in the mineral salts in that have a role to play in tinnitus, NIHL, and AIHL. It doesn't have anything to do with serotonin, but i know some of you wanna die on that hill.

Agmatine quite consistently lessens my tinnitus considerably whenever i take it. Anything dopaminergic increases my tinnitus tenfold as dopamine and glutamate are very inter-connected. There's no room for debate here for me

What makes you think serotonin isn't involved?

Serotonergic Regulation of Excitability of Principal Cells of the Dorsal Cochlear Nucleus

The dorsal cochlear nucleus (DCN) is one of the first stations within the central auditory pathway where the basic computations underlying sound localization are initiated and heightened activity in the DCN may underlie central tinnitus. The neurotransmitter serotonin (5-hydroxytryptamine...

www.jneurosci.org

Our findings reveal that 5-HT exerts a potent influence on fusiform cells by altering their intrinsic properties, which may enhance the sensitivity of the DCN to sensory input

Some serotonin receptors can stimulate glutamate release (and thus atleast indirectly cause tinnitus if we believe glutamate is the direct cause).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430669/

By activation of 5-HT3 receptors, instead, 5-HT stimulates the release of either glutamate [7, 57, 185] or GABA [90, 96, 179]. Also 5-HT2 receptors were shown to stimulate GABA release [2] and to either increase [2, 72, 177] or reduce [118] glutamate release in distinct structures.

 

[SaltiestSardine]

none of what you quoted says what you think it says if you read the rest of the paper. all it's really saying is that serotonin has an involvement in the auditory cues of sound localisation and heightening auditory sensitivity. nowhere does it imply that serotonin is directly involved in tinnitus. i'm forum illiterate and don't know how to format the way you do otherwise i would quote the relevant points to show you how you most likely are taking that paper in a direction that itself is not implying.

In my own experience at least, whenever i focus on dopamine or dopaminergics the test for my hearing threshold always comes back as not as good as the previous months. i've worked in professional audio for over 15 years and I am intimately familiar with my own hearing and can immediately tell when something is off. to say that i am paranoid about hearing is an understatement. i get tests at least 3-4 times a year and i get them done privately as the one on the NHS is absolutely ******* useless and doesn't account for anything outside of speech recognition which only requires hearing up to about 7-8khz and ridiculously high hearing thresholds that do not even equate to half the dynamic range of the human ear. that is practically deaf as far as i am concerned. anyways... a pattern i noticed consistently with the results is my hearing threshold in the upper frequencies would drop quite markedly on the months i focused on dopamine.

When i started incorporating more oily fish(omega 3), and looking at neurotransmitters more holistically rather than this myopic "this neurotransmitter bad. this neurotransmitter good"is only when i started to move the needle with my own tinnitus and hearing fatigue. it's still there, but i have to make myself actively aware of it to notice it as it's whisper quiet almost. when i am in the middle of a mixdown i never notice it anymore and my threshold for hearing fatigue has extended into the hours, rather than 20-30 minutes like it used to be since i started focussing more on dietary magnesium, Agmatine, adaptogens and being mindful of my blood sugar. Gingko Biloba has helped a lot too by providing more blood flow to the cochlear. if you are going to go that route though i would only get it from Nootropics depot. I always thought that Gingko Biloba gave me splitting headaches, but now i realise it was probably just the piss poor quality of a lot of Gingko on the market. i only buy supplements from Nootropics Depot these days as they are the only ones i know of who do not only 3rd party testing, but batch test every single batch before they put it out.