Ototoxicity Part 3 - Gut dysbiosis, Gut-Inner Ear Axis, TRPA1 channels & Chimeric spike risks to hearing and balance.
Hypoxia, Heat or cold extremes can damage hearing - TRPA1 channels may be why. Happy New Year's Eve!
Hearing loss has been linked to the CoV era. Dizziness was a frequent symptom of SARS-CoV-2 infections and vestibular dysfunction did occur in some people who were studied but it didn’t seem to be a widespread problem. (Zubitzer, et al., 2023) Alopecia and hearing or taste loss have been common following CoV era infection or injections. Cerebral Small Vessel Disease may be involved. Cerebral blood flow may be decreased up to 25% in Alzheimer’s dementia. Permeability of the blood brain barrier increases. (Li, et al., 2018) The inner ear also has a membrane barrier that should filter out larger toxic molecules when it is functioning correctly.
“The main clinical manifestations of CSVD include stroke, cognitive decline, dementia, psychiatric disorders, abnormal gait, and urinary incontinence.” […] “Conventional risk factors such as hypertension diabetes, smoking, high homocysteine concentrations, obesity, and dyslipidemia have been considered to lead to arteriolosclerosis. In addition, hematological disorders, infection, and hereditary diseases are increasingly recognized in various studies10,11.” […]
“SVD is thought to be among the main causes of vascular cognitive impairment, and is thought to account for about 45% of dementia cases, which is also associated with so-called silent lacunar infarcts which are asymptomatic infarcts with definite lesions on neuroimaging57–60. Cognitive decline caused by CSVD presents with executive dysfunctions, attention and memory decline, set-shifting disabilities, slower speed of information processing, decline of verbal fluency, and delayed recall. On the behavior area, symptoms showed apathic, mood disorder, depression and daily living disability1,54,56. Among others, some clinical features include sleep disorders, vertigo, tinnitus, and hearing disorder.” (Li, et al., 2018) *link via Walter M. Chesnut, (x.com/Parsifaler)
Ototoxicity and Balance, Part 1: (Substack), Part 2: (Substack). This post is part 3 and there will be a part 4 with a focus on autoimmune disease as underlying risks for hearing damage or tinnitus.
Gut dysbiosis and our “Gut-Inner Ear-Brain Axis”
Gut dysbiosis can lead to a lack of nutrients that beneficial species make for us (and them) and an excess of negative chemicals that may have toxic effects on the body’s level of inflammation or impact our mood negatively. The “Gut-Inner Ear-Brain Axis” is a new area of study as we are learning how our gut microbiome is intertwined with brain and general health… and with our hearing too! (Graham, et al., 2023)
Chimeric spike issues are significantly impacting the balance of beneficial to negative species in the gut. It seems to selectively kill the helpful Bifidobacterium species. Work by Dr. Sabine Hazan with fecal screening of patients before and after CoV proved that the “Bubble Tea” meme theory was correct. A meme based on a real graph of CoV infection rates suggested that the reason why Asian nations didn’t get as sick from early outbreak CoV in 2020 compared to Western nations was the difference in use of tapioca rich foods like the ‘bubbles’ in Bubble Tea.
For more about Bubble Tea and ‘Covid’, see page Resistant Starch/Butyrate on jenniferdepew.com.
For more on chimeric spike’s effects on Bifidobacterium species and Dr. Hazan’s work, see this post, Bifidobacterium, CoV, Sabine Hazan, and butyrate producing colon species. “Feed them well and you are feeding yourself well too! Vitamin C, D, zinc, inulin, arabinoxylan, and pomegranate peel help support bifidobacterium and butyrate producing species of the microbiome.” (Substack).
Androgenic alopecia may also be related to Cerebral Small Vessel Disease. Microbiome changes on the skin may be a factor. (English, 2018, via x.com/Parsifaler) Fecal microbiota transplant has helped improve hair growth on the scalp in two patients with alopecia areata and Clostridium difficile gut infections. (Rebello, et al., 2017) Could fecal transplant help people with hearing loss or tinnitus? Maybe, Dr. Hazan said she can’t talk about that right now, suggesting she has an academic paper in the works on the topic, or is considering that. *Academic publishers want a paper to be brand new material - secret until published in their journal. If you have the financial resources to support Dr. Hazan’s largely self-funded work, please donate at her website, microbiomeresearchfoundation.org. (x.com/SabinehazanMD)
Pomegranate products help support the beneficial gut species and is a broadspectrum antimicrobial for bacteria and Candida yeast and other pathogens. Pomegranate juice is so effective for promoting a healthy microbiome that it was found to be an effective replacement for tooth-brushing or mouthwash - swish an ounce or two of pomegranate juice in the mouth for a minute and “Look Mom, no more cavity promoting pathogenic oral microbiome species!” Pretty nifty that a fruit juice can help protect against cavities - by resetting the mouth microbiome towards healthy species.
Aside: Breast cancer seems to be related to tooth or gingivitis issues - the lymphatic drainage from the mouth flows through the breast tissue area.
“Porphyrins are a byproduct of Propionibacterium acnes (P. acnes), a commensal microorganism found in the skin biome which colonize sebaceous ducts, ingests sebum, and are implicated in acute inflammation and acne onset [108]” (English, 2018)
Intestinal gut dysbiosis affecting a “gut-inner ear axis” may be a factor in sensorineural hearing loss (SNHL). Protective against SNHL: Lachnospiraceae (UCG001) are butyrate producers who want resistant starches and fiber in your diet (Vacca, et al., 2020), and Intestinimonas species are also a butyrate producing species that convert Nε-fructosyllysine and/or the amino acid lysine into butyrate. (Bui, et al., 2020) While Rikenellaceae (RC9gutgroup) and Eubacterium (hallii group) species seem to increase risk for sensorineural hearing loss. SNHL is associated with risk for later dementia or other cognitive disorders. (Yin, et al., 2023)
Rikenellaceae (RC9gutgroup) are Gram-negative bacteria found in the gut more frequently in people who are “leptin-resistant obese and diabetic.[4]” (Wikipedia)
Eubacterium (hallii group) are anaerobic, Gram-positive, catalase-negative bacterium from the family Firmicutes, which in excess are associated with obesity. Pomegranate products may help promote more Bacteroidetes in ratio to Firmicutes species. (George, et al, 2019)
A high-fat diet promotes more of the negative obesity-linked species. Microbiome health can be worsened towards an obesogenic profile by high fat diet and there is cross talk between the lungs and gut, a gut-lung axis in addition to the gut-brain axis. (Bruno, et al, 2021) Gut dysbiosis can negatively impact our skin, our teeth, and our inner ear health too. Chemicals produced in the gut end up circulating throughout the body, including the inner ear. Inner ear has three layers of protection, the blood-labyrinth barrier, the cerebrospinal fluid-labyrinth barrier, and the middle ear-labyrinth barrier. (Juhn, 1988)
The membrane barriers should help keep toxic chemicals out of the inner ear, similarly to the blood-brain-barrier, but the inner ear membranes can become ‘leaky’, too. Gluten, dairy, and soy proteins may increase ‘leakiness’ of the tight junctions between the cells of membranes. Once the dietary proteins ‘leak’ into the bloodstream, they may circulate throughout the body and increase membrane leakiness at the blood brain barrier or other membranes. Celiac disease or gluten intolerance may co-occur with sensorineural hearing loss but it is not a strong link.
Pomegranate peel seems to act as an antimicrobial against negative species while also promoting the growth of beneficial species, making it more effective and safer than using traditional antibiotics for gut dysbiosis or oral cavity producing pathogens. Pomegranate peel extract has also shown topical benefits against HIV-1 risk - a topical anti-STD product? It likely needs financial backing.
“Sensorineural hearing loss (SNHL) is the most common type and accounts for the majority of all hearing loss, which is characterized by irreversible damage to cochlear hair cells, auditory nerves, or the central nervous system (Tanna et al., 2020). SNHL is also associated with dementia, Alzheimer's disease, and other cognitive disorders (Hung et al., 2015; Fortunato et al., 2016; Shen et al., 2021). Although the pathogenesis of SNHL is still not fully understood, a variety of causes, including genetic factors, aging, chronic noise exposure, ototoxic medications, and head injury, are believed to be involved (Chau et al., 2010; Kuhn et al., 2011; Tarshish et al., 2013). Moreover, obesity and a high-fat diet have also been linked to hearing loss (Tang et al., 2019; Kociszewska et al., 2021).”
‘A triage guide for tinnitus’, The Journal of Family Practice, a pdf, (Henry, et al., 2010).
A success story and herbal recommendation for vascular related tinnitus or hearing issues:
“The noise in my head disappeared, and my blood pressure returned to normal... and I cured my bladder and kidneys without pills!
Tinnitus is a fairly common ailment, so this symptom should not be ignored. It may indicate the onset of sclerosis, brain and vascular diseases! By the way, tinnitus occurs along with high blood pressure. Pharmaceuticals help to lower blood pressure, but do not relieve the cause, and pills can lead to unpleasant side effects!
This plant helps to normalize blood pressure, relieves headaches, heals wounds, improves gastrointestinal function, treats kidneys, bladder, and liver. Horsetail should be used to cleanse blood vessels as follows:
Heathersweet potato leaves - 1 tsp. Water - 1 glass. [*Literally leaves from a sweet potato plant, species “Heathersweet”. Horsetail is a different herbal remedy, I’m not sure if two remedies are intended.]
Pour cold water over the leaves in the evening. Strain the tincture in the morning. Drink 2 tbsp 4 times a day, 30 minutes before meals.” - Barbara O’Neill, (x.com/BarbaraOneillAU)
‘Sweet Potato Leaves: Edible, Flavor, Nutritional And Medicinal Benefits’,
May 15, 2023, By: Mitch Baylis, (gardenersmag.com)
‘Sweet Potato Leaf Tea’, (teaalmanac.com)
Horsetail - a fern used medicinally to promote hair growth and bone health. It is a source of silicon. (healthline.com). If taking horsetail as a supplement, then taking thiamin, vitamin B1, is recommended too, as horsetail use may deplete B1 levels. (mountsinai.org) Using diatomaceous earth to make structured water would be providing silicon/silica too but not necessarily a well-absorbed form of silica. It is used to support hair, skin and nails, teeth and bones. (webMD.com) Anecdotally, silica can help with vertigo, headaches, tinnitus (a buzzing or ringing in the ears), and sleep deprivation.
A homeopathic remedy: “Natrum salicylicum is a useful remedy when tinnitus and tiredness occur after influenza or along with Meniere’s disease.” (peacehealth.org) Homeopathic remedies that are properly made are nanoparticle preparations of the original substance which is something that causes symptoms. Use of the tiny nanoparticle amount of the toxin seems to stimulate the body into ‘fighting’ that symptoms. Natrum salicylicum is a homeopathic remedy made from sodium salicylate. (drhomeo.com) Salicylate excess can be a cause of tinnitus or hearing damage, so the homeopathic principle of ‘Like treating Like’ may be in play.
Homeopathy and herbal remedies may seem out in left field, however, patients with tinnitus are frequently told that they just have to live with it. Epsom salt soaks for a topical magnesium source helped me to resolve tinnitus, and eyelid twitching also occurred around that time. Magnesium adequacy helps calm a contracted muscle. Chronic muscle knots may involve a lack of magnesium, or excess calcium and phosphorus in ratio to magnesium. Gut problems can interfere with magnesium absorption while allowing calcium absorption. Calcium causes muscles to contract and can add to oxidative stress and excitotoxicity risks.
Oxidative stress produces more of the inflammatory signaling TGF beta, TNF alpha and NF-kB. Pomegranate peel or other polyphenols and Nrf2 promoting foods like omega 3 fatty acids would help inhibit those chemicals and prevent worse escalation of a positive feedback hyperinflammation loop.
Promoting Nrf2 also is inhibiting TNFalpha which is important because inflammatory TNFa promotes more expression of TRPA1 channels (Liu, et al., 2020; Talavera, et al., 2020)) which can lead to more symptoms as more channels are available to be opened to flood the cell with stimulating calcium.
“The proinflammatory cytokine tumor necrosis factor-α (TNF-α) elevated the plasma membrane content of TRPA1, TRPV1, and the calcitonin gene-related peptide (CGRP).” (Talavera, et al., 2020)
Are TRPA1 ion channels a common factor in hearing and dementia risks? Increased calcium can open them leading to more calcium entry into cells which causes over-activity and can lead to cell death from excitotoxicity (see Part 1). Magnesium helps keep some types of TRP channels closed. Oxygen level changes and high (49’C) or low temperatures (4’C) increases expression of TRPA1 channels. They don’t function if the ankyrin repeat domain, coil-like section is broken.
“TRPA1 is therefore activated by both hypoxia and hyperoxia, displaying minimal basal activity at O2 concentrations close to the physiological values. Interestingly, this type of modulation may impact the activation of the channel by several factors.” […]
“More recently, total internal reflection fluorescence microscopy and density gradient centrifugation experiments revealed that TRPA1 localizes preferably into cholesterol-rich domains (763). Depletion of cholesterol with an extracellular MCD treatment decreased the maximal response of TRPA1 channels to AITC and reduced the sensitivity of TRPA1 to chemical stimulation with AITC (a 5-fold increased EC50).” (Talavera, et al., 2020)
*More on the role of cholesterol in hair cells and our hearing is in the final section of this post - Statin medications can have ototoxic effects in some people but also can be protective of hearing or reduce tinnitus in a person with elevated blood cholesterol.
Hyperpyrexia is a fever that is unusually elevated and risky and generally occurs in children rather than adults. Childhood illnesses with fever may cause hearing damage because of the body temperature above 106’F which is about 40.5 or 41’ C. Higher frequency sound and higher body temperature (above 102’F) was associated with more damage to the inner ear cochlea in a study on children with childhood fever. (Murthy and Spandana, 2018)
“Hyperpyrexia is more common in children than adults.19 It may result from the increased heat production that occurs following the uncoupling of oxidative phosphorylation. Additionally, toxic levels of salicylate impair the efficiency of the body's cooling mechanisms.” (ScienceDirect)
*See Part 1 for more on salicylate ototoxicity.
A high fever may be damaging to hearing by increasing oxidative stress chemicals in general. A respiratory infection with congestion in the ears might physically be increasing pressure in the inner ear and cause damage.
TRPA1 channels are involved in the mechanics of our hearing and TRP channels with ankyrin domains may be at risk from chimeric spike.
The role of TRPA1 channels within hearing is discussed more later, first a bit more about viral infections and the chimeric spike’s potential harm via TRP channels that have ankyrin repeat domains. TRPV and TRPC channels also have ankyrin repeat domains but a shorter series than TRPA-1. It is a series of ankyrin protein subunits that form a coil like shape when linked together. The flexibility of the coil helps with sensing temperature or oxygen. TRPA-1 channels won’t work without the coil-like ankyrin repeat domains. Motion and varied chemicals (varies with the type of channel) can also activate TRP channels.
“Say what? SARS2 infection of the inner ear may cause hearing and balance issues.
Human inner ear tissue expresses ACE2, TMPRSS2, and FURIN - all necessary for SARS2 virus entry. Microscopy confirms the infection of hair cells and Schwann cells by SARS2.” - David Lingenfelter, PhD, @dlingenfelter, (x.com/dlingenfelter)
Direct SARS-CoV-2 infection of the human inner ear may underlie COVID-19-associated audiovestibular dysfunction. (Jeong, et al., 2021)
Say… Pomegranate Peel Extract.
Pomegranate peel phytonutrients would help prevent entry of the SARS-CoV-2 virus or chimeric spike at the ACE2 and TMPRSS2 receptors and would also block the Furin cleavage site. It is effective against the HIV-1 AIDS virus too. It is also protective of Hair Cells from being damaged by Aminoglycoside Ototoxicity. More on how pomegranate peel extract might help is included later.
The balance issues are from dysfunction in our vestibular system of the inner ear, which has motion detecting Hair Cells. Another example of vestibular dysfunction after CoV era: ‘Acute Bilateral Vestibulopathy Associated With COVID-19’, Lee, et al., 2022 - treatment was “vestibular rehabilitation at home”, and the patient was restored to function at a five month follow up. (Lee, et al., 2022)
Videos at Vestibular.org, Vestibular disorders have dizziness or loss of balance symptoms and it can become exhausting as the body is over working or over compensating trying to be steadier.
“VERTIGO - Clinical differentiation between Benign Paroxysmal Positional Vertigo, (BPPV), Cerebellar Stroke, and Vestibular Neuritis.” – Dr. Akhil, (x.com) Image from the Telegram channel: t.me/Oxfordhandbookk/126.
Ototoxic effects on Hair Cells of the inner ear can lead to hearing loss or tinnitus buzzing, but it can also affect Hair Cells in the vestibular system, affecting sense of balance and increasing risk of falling or vision changes – trouble tracking moving objects with focus. The ball may hit you instead of you being able to catch it. Eye-hand coordination is complex needing a variety of areas of the brain and body to function smoothly together. (Hair cell basics, Wikipedia) Hair cells don’t appear to wave so much as pulse in time to the sound - “Hair cell dancing to Rock Around the Clock” (auditoryneuroscience.com).
The ototoxic antibiotic kanamycin may have been in Pfizer CoV injections (x.com/groovedodger1) and it is known to risk the Hair Cells within the hearing area more than those in the vestibular system and cause hearing loss without effecting sense of balance too. (emedicine.medscape.com)
Additive effects of loud noise, other stress, and nutrient deficiencies would increase risk of damage to Hair Cells. And a co-infection with another virus might be an added factor in hearing loss. Hair Cells or other damage can cause short term or long-term hearing loss. Adequate treatment of the infection can help reverse some types. (Cohen, et al., 2014) Co-infections are common with SARS-CoV-2 infection or following CoV injection changes in immune function and T-cell types.
Viral Infections with a history of hearing loss effects:
“Viral infections, in particular cytomegalovirus (CMV), cause up to 40% of all congenitally acquired hearing loss. Many viruses can be the cause of congenital or acquired hearing loss (Table 1). Typically, viruses cause sensorineural hearing loss (SNHL); however, a viral etiology has been proposed for otosclerosis. Infection with HIV can lead to conductive hearing loss (CHL) through bacterial and fungal infections, which become more frequent following the immunosuppression caused by that virus. Hearing loss caused by viruses can be mild or severe to profound, unilateral or bilateral. Mechanisms involved in the induction of hearing loss by different viruses vary greatly, ranging from direct damage to inner ear structures, including inner ear hair cells and organ of Corti (as seen in some of the classically described causes of viral hearing loss such as measles), to induction of host immune-mediated damage (Table 2). Following infections with certain viruses, hearing loss can be reversed or limited by appropriate antiviral therapy.” – ‘Viral causes of hearing loss: a review for hearing health professionals.’, (Cohen, et al., 2014)
The chimeric spike of SARS-CoV-2 or the CoV injections may have ototoxic effects and the pressure sensing TRPA1 channels may be a point of damage – at the ankyrin repeat domain, a repeating series of ankyrin protein subunits which stack into a spring like structure that can respond to pressure changes – is the spring more relaxed or more squished together? …roughly.
TRPA1 channels and the Ankyrin Repeat Domain – a coil-like protein formed from repeating ankyrin subunits.
If it is surprising to learn that we have tiny springs in our ears that help us to sense sound waves, then you’re welcome, or what did you expect was in there? Little tiny microphones?
Side trip into a Recording Studio to look at full-size microphones:
How Microphones Pick Up Sound
In a recording studio, sound is picked up by microphones, which convert acoustic energy into electrical signals. Here’s a breakdown of the process:
Microphone Operation: Regardless of type, microphones work on the same principle:
Sound Waves: Sound waves from the source (e.g., a singer, instrument, or room ambiance) reach the microphone.
Diaphragm: The sound waves cause a thin diaphragm (usually made of metal, plastic, or Mylar) to vibrate.
Coil: The vibrating diaphragm is connected to a coil of wire, which is suspended in a magnetic field.
Electromagnetic Induction: As the diaphragm vibrates, it induces an electromotive force (EMF) in the coil, generating an electrical signal.
Output: The electrical signal is sent through a cable to a preamplifier, mixer, or recording device, where it’s amplified and processed. (More on Microphones, Brave AI)
Diagram of a simple moving coil microphone, (Brave AI summary):
+---------------+ | Diaphragm | +---------------+
|
|
v
+---------------+ | Coil (Wire) | +---------------+
|
|
v
+---------------+ | Permanent | | Magnet | +---------------+
|
|
v
+---------------+ | Electrical | | Output (Signal)| +---------------+
Do we have magnets in our ears too?
Electromagnets? - an electrical field will create a magnetic field as long as the electricity is present. The basolateral membrane of the Hair cells in non-mammals is electrical. (Hair cell, Wikipedia) Nerve signaling involves a shift in polarity across a membrane potential.
“An electromagnet is a type of magnet in which the magnetic field is produced by an electric current. Electromagnets usually consist of wire wound into a coil. A current through the wire creates a magnetic field which is concentrated in the hole in the center of the coil. The magnetic field disappears when the current is turned off. The wire turns are often wound around a magnetic core made from a ferromagnetic or ferrimagnetic material such as iron; the magnetic core concentrates the magnetic flux and makes a more powerful magnet.” (Electromagnet, Wikipedia)
Calcium flow in and out of hair cells is key in the mechanical transduction of motion into a nerve signal. Calcium binding proteins help control the calcium.
“Many types of hair cells are intensely labeled by fluorescent antibodies against one or more of the diffusible calcium-binding proteins calbindin-D28k, calretinin, parvalbumin-α, and parvalbumin-β (also known as oncomodulin or PV-3).” - Audition, M.A. Rutherford, W.M. Roberts, in The Senses: A Comprehensive Reference, 2008, 3.22.3 Hair Cells, Viewable at ScienceDirect.
“Well, isn’t that interesting.” - The Church Lady, SNL — this post took a sudden turn into autoimmune disease as a cause of hearing loss, and albumin/egg or nut food sensitivity might be a molecular mimicry cause. I’m moving that to another post, Part 4.
TRPA1 channels and Hearing
Back to our ears… TRPA1 channels and their spring-like ankyrin repeat domain sections are acting like the coil in a studio microphone.
It turns out that we do have tiny microphones in our ears… and there are also many medications known to damage the TRPA1 channels or other effects on Hair Cells. A list of medication and other known ototoxins is included in Part 2.
Disruption of TRPV-1 channel function by spike protein due to the ankyrin repeat domains may affect a variety of functions in the body including hearing and cause other symptoms resembling Covid19. Liviero, et al, noted the TRPV1-like symptoms and suggests trying TRPV-1 inhibitors or down-regulators, (Liviero, et al, 2021), however TRP channels have multiple functions and just inhibiting them has not worked for other conditions. It is being suggested here if lung function is impaired and not clearing the infection. Citrus peel consumption helps clear out lung congestion due to the bitter taste receptor effects. See Part 1.
“The discovery that S protein includes two ankyrin binding motifs (S-ARBMs) and that the transient receptor potential vanilloid subtype 1 (TRPV-1) cation channels contain these ankyrin repeat domains (TRPs-ARDs) suggest that TRPV-1, the most studied member of the TRPV channel family, can play a role in binding SARS-CoV-2. This hypothesis is strengthened by studies showing that other respiratory viruses bind the TRPV-1 on sensory nerves and epithelial cells in the airways. Furthermore, the pathophysiology in COVID-19 patients is similar to the effects generated by TRPV-1 stimulation. Lastly, treatment with agonists that down-regulate or inactivate TRPV-1 can have a beneficial action on impaired lung functions and clearance of infection.” (Liviero, et al, 2021)
Pomegranate peel would help block chimeric spike in other ways. Methyl B12, zinc and magnesium may be protective for hearing. Saffron may help and adequate protein. Word of mouth feedback – tuna fish regularly in the diet helped restore taste sensations. It is a good source of methyl B12 and zinc and protein.
The green subunits of the TRP channel in the graphic below, would cluster together in a petal flower like bundle and form a channel around the Helix pore.
TRPV-1 channels have an ankyrin repeat domain like TRPA-1 channels. It may help with sensing high temperature. (Ladrón-de-Guevara, et al., 2019) This may put these TRP channels at risk for chimeric spike to lodge in them because of ankyrin repeat like sequence in the spike. Activating them would lead to unwanted symptoms from over activity of cell activity or nerve signaling. (Liviero, et al, 2021)
TRPA channels have more ankyrin repeat domains - a longer coil would form, TRPV have some and TRPC just a few.
TRPA-1 is the only member of that subgroup of TRP channels.
Possibly related to a synthesized chimeric spike with ankyrin repeat domain sequences… or a coincidence. Synthesized ankyrin repeat domains are in use in cancer research.
“We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition.” (Balakrishnan, et al., 2019)
~~
The ankyrin repeat domain is not necessary for pressure sensation by the TRPA1 channels, a change in oxidation potential will signal mechanical energy.
“The TRPA1 N-terminal ankyrin repeat domain is not required for mechanosensation. The TRPA1 mechanosensitivity is dependent on its redox state.” (Moparthi and Zygmunt, 2020)
Then what does the Ankyrin Repeat Domain in TRPA1 Channels do for our hearing?
The ankyrin repeat domain (ARD) in TRPA1 channels of inner ear hair cells plays a crucial role in mechanotransduction, the process by which hair cells convert mechanical stimuli into electrical signals. The ARD is a unique feature of TRPA1 channels, consisting of 17 ankyrin repeats at the cytosolic N-terminus. This domain helps us with:
Mechanical elasticity and adaptation to changing forces.
Mechanical force transmission and conversion into electrical signals.
Ca2± sensing.
Ligand binding and response to toxins or irritants, and pain.
Temperature and oxygen sensing.
“Ankyrin repeats are found in many types of proteins besides TRP channels, including several large families of transcription factors (e.g. NFκB and Notch) and regulatory proteins (e.g. cyclin-dependent kinase inhibitors) for example.” (Gaudet, 2008)
Functions of the coil-like Ankyrin repeat domain of TRPA1 ion channels within Hair cells:
A primer on ankyrin repeat function in TRP channels and beyond. (Gaudet, 2008)
Ankyrin repeat domain regulation of the TRPA1 channel. (Zayats, et al., 2013)
Transient receptor potential channel melastin (TRPM) 1-8 and ankyrin TRPA1 in mouse inner ear. (Takumida, et al., 2009)
Mechanical elasticity: The ARD provides mechanical elasticity, allowing the channel to stretch and deform in response to mechanical stimuli, such as sound waves or vibrations. This elasticity enables the channel to maintain its functional state and adapt to changing mechanical forces.
Ca2±sensing: The 12th ankyrin repeat is thought to form an EF-hand-like Ca2±sensing domain, which detects changes in intracellular Ca2+ levels and modulates channel activity. This Ca2±dependent regulation is essential for fine-tuning mechanotransduction in response to varying sound intensities.
Ligand binding: The ARD also contains cysteine residues that form ligand-binding pockets, allowing TRPA1 to respond to covalently modifying electrophilic compounds, such as pungent chemicals or reactive oxygen species (ROS). This property may contribute to the channel’s ability to detect and respond to toxins or irritants in the inner ear environment.
Mechanical force transmission: The ARD may facilitate the transmission of mechanical forces from the stereocilia to the channel, enabling the conversion of mechanical energy into electrical signals.
Protective against acrolein, a glycated protein (AGE): (Sakamoto, et al., 2023) – TRPA1 channels mediate cytotoxicity from the AGEs acrolein.* More info on AGEs is included later.
Pain sensors: (Nagata, et al., 2005) TRPA1 ion channels send pain signals and don’t stop within the ear. Returning signals from the brain can help the inner ear to muffle itself a bit against loud noise and become less responsive - auditory regulation via the coordinated TRP channels, bitter taste receptors and NMDA or other receptors located on the base membrane of the hair cells.
Vascular function: (Alvarado, et al., 2021)
Temperature and oxygen sensors: (Talavera, et al., 2020)
*RAGE, Receptor for Advanced Glycation End-products. Advanced Glycation End-products, AGEs, are glycated proteins - sugar combined with a protein in a high heat reaction - broiling or baking or high heat extrusion of snack foods or breakfast cereals. AGEs are also created in greater amounts within the body during oxidative stress. The proteins become dysfunctional with sugar attached and can have negative effects on health.
Dietary AGEs can be tasty and in our favorite foods as crispy caramelized coating on barbecue or baked goods but may be a cancer risk. RAGE is a receptor found on many cell types, including endothelial cells, smooth muscle cells, and immune cells, activation by an AGEs or other ligand, triggers inflammatory responses and further oxidative stress. This is seen in diseases including atherosclerosis and complications of diabetes.
Treatments
We can’t really regrow the Hair Cells naturally, though new treatments have been learned which may help us to do so. “Researchers discover a drug combination that can regenerate hair cells in the inner ear.” 2017, The WNT pathway is stimulated to promote more support cells which can differentiate into Hair Cells. (news.mit.edu) Caspase enzyme inhibition may be a strategy for promoting Hair Cell growth. (Ku, et al., 2014) Pomegranate peel extract is a caspase-3 inhibitor (Brave AI summary) and can inhibit or possibly modulate the WNT pathway which is studied because that is protective against proliferation of cancer cells. (Brave AI different summary)
Prostacyclin and Adrenochrome accumulation as a risk for schizophrenia.
A metabolite of Arachidonic Acid, prostacyclin, may help hearing loss due to sudden sensorineural hearing loss (SSNHL), but it is not understood why other than helping improve blood flow to the ear. Moderate benefit, inconclusive results or positive results were achieved with use of the prostaglandin prostacyclin for SSNHL. (Olaf and Ronald, 1991; Stitham, et al., 2011)
“Prostaglandin (PGE1) and prostacyclin (PGI2) or their analogues were also tested in clinical studies on ISSNHL. While Nakashima et al. (1989, PGE1), Michel and Matthias (1991, prostacyclin analogues) and Ogawa et al. (2002, PGE1) found no benefit of these drugs in placebo controlled or therapy comparison studies, Olszewski et al. (1990) reported a clear superiority for prostacyclin (PGI2) compared to placebo [33], [34], [35], [36]. It must be noted here that PGI2 in particular also exerts a thrombocyte aggregation inhibiting effect.” (Plontke, 2005)
The link between schizophrenia and hearing may help explain - people with schizophrenia may be accumulating adrenochrome and adrenochrome inhibits production of prostacyclin - but not everyone with excessive stress convert a majority of adrenalin into adrenochrome or can’t break down adrenochrome if it is made, so prostacyclin might not help all patients with hearing symptoms equally. It may help those people who don’t have enough prostacyclin and not be needed by other people. Adrenochrome made cultured human umbilical arterial endothelial cells produce less prostacyclin. Cholesterol uptake was increased compared to control or epinephrine exposure and DNA uptake of radioactive labeled thymidine was decreased. (Zhou, et al., 1995)
“We suggest that atherogenic changes found in severe hypertension may be due to abnormal high concentration of epinephrine, especially oxidized epinephrine, on endothelial cell functions, such as DNA synthesis, cholesterol uptake and prostacyclin production.” (Zhou, et al., 1995)
Medical research seems to have a blind spot regarding the research into adrenochrome and schizophrenia by Abram Hoffer, et al.. Or medical research in the area of adrenochrome’s role in health and illness is being suppressed or not funded.
See this post for the biochemistry of adrenochrome and how it relates to schizophrenia. Nutritional guidance for improving health by reducing adrenochrome accumulation is included. A data dump is also included regarding CYM company, which seems to be actively harvesting children’s blood for sale as an adrenochrome product. (Substack)
The short story on Adrenochrome, schizophrenia and a dietary approach to reduce adrenochrome accumulation - you’re not going to be able to ask your doctor about this as it is not standard information. This is my deep-dive on the topic based on Hoffer and Osmund’s research and lengthy book chapter (linked in the post if you want to read it) and more recent related research on functional health or schizophrenia.
Schizophrenia seems more of a symptom or syndrome with many causal factors that may or may not individually be a problem but can add to the symptom set of no longer recognizing internal voices as your own, or be able to exclude irrelevant sensory input from attention - everything seems related and important - they are out to get me! Paranoia and reckless behavior with indifference to consequences are symptoms of adrenochrome excess. The person also seems unaware that they are the changed person in the room. Longer exposure to adrenochrome testing or randomly, some people were left with lingering personality changes after trying the newly discovered metabolite of adrenalin. Adrenochrome is the oxidized form of adrenochrome.
A person with functioning methylation cycles and sulfation would be processing adrenalin into safer chemicals than adrenochrome. Someone at risk for adrenochrome accumulation may not process niacin well and need the high doses that Abram Hoffer found clinically helpful for schizophrenia treatment.
Oxidative stress would be increasing adrenalin and inflammatory signaling chemicals in anyone, and be a risk to hearing… some people may convert more of it to adrenochrome than average and be at increased from adrenochrome inhibiting prostacyclin production, cholesterol uptake, and DNA synthesis. (Zhou, et al., 1995)
We’re not done yet, you’re awesome for being here. You now know more neuroscience and biochemistry than most people.
Adrenochrome inhibits “Cholesterol uptake.” (Zhou, et al., 1995)
The inhibition of cholesterol may be a key point in risk to hearing from excess adrenochrome, more than prostacyclin inhibition.
Drum roll… we also have little drums in our inner ear hair cells. The membrane of the hair cell is part of motion sensing and amplifying of the sound wave or head motion and it contains cholesterol and phospholipids. Cholesterol in the cell membrane also helps coordinate the various receptors and ion channels that support the mechanotransduction nerve signal of the hair cell. Cholesterol is part of the structure of the stereocilia - the ‘hairs’. Cholesterol is like a Lego building block for the hair cell’s critical structures. Upsetting balance of cholesterol within the body towards too little or too much may damage hearing. Statin drugs are probably damaging to hearing. Me guessing.
The answer is - yes it may be a risk. I need to add it to the Part 2 list of ototoxins. However if you have high cholesterol, statin use may help reduce risk of hearing loss or tinnitus. Individualized care is needed here. Someone with elevated adrenochrome inhibiting their body’s uptake of cholesterol may be more at risk for ototoxic effects from a statin medication than someone who has elevated levels of blood cholesterol.
Ototoxity causing Irreversible Hearing Loss and Tinnitus: A case report describes a 32-year-old man who developed irreversible, progressive hearing loss and tinnitus after 18 months of atorvastatin therapy for hypercholesterolemia. The hearing loss was characterized by a “cookie-bite” pattern, affecting middle frequencies bilaterally. “Four years after drug discontinuation, his hearing loss had neither progressed nor regressed. […] The manufacturer of atorvastatin has received three unpublished cases of deafness, but claims that causal relationships were not established.” (Liu, et al., 2012)
Cholesterol medications and atorvastatin specifically, are included in this list of medications with ototoxic risks. (americaspharmacy.com)
Use of Atorvastatin along with cisplatin treatment was protective against the ototoxic effects of cisplatin. (Fernandez, et al., 2021) Add some capsaicin for a modulatory effect from bitter taste receptors maybe (discussed in Part 1). (Ramkumar, et al., 2022)
Tinnitus: Atorvastatin is the only statin associated with causing tinnitus among the various 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, however dizziness is reported with the entire family of statin drugs and rosuvastatin (Brand name Crestor) may have ototoxic effects too. (hearinglosshelp.com)
Hyperlipidemic patients: For individuals with high cholesterol, protective effects may be seen with statins, including atorvastatin, rosuvastatin, and simvastatin. Statin use was somewhat helpful for hearing and rosuvastatin 10 mg or 20 mg reduced tinnitus in hyperlipidemic patients. (Yücel , et al., 2019)
National Health Screening Cohort: A study involving a national health screening cohort in Korea did not find a significant association between statin use and hearing impairment. The patients were over 70 on average and those with hearing impairment were found to have used 11% less statin medication than those without hearing impairment, so there almost a protective effect shown. The number of days of previous statin use was not significantly different between the hearing impairment group and the control group (adjusted odds ratio [aOR] = 0.94, 95% confidence interval [CI] = 0.86–1.02, P = 0.118). (Kim, et al., 2021)
Type 2 Diabetic Patients: Research indicates that statin use in type 2 diabetic patients significantly reduced the risk of sensorineural hearing loss (SNHL) or tinnitus by 24.8% (95% CI 14.2–34.1%, p < 0.001) after controlling for confounders. The use of statins was associated with a reduced risk of SNHL, regardless of age and sex. (Han, et al., 2021)
We’ll save phospholipids, and autoimmune antibodies against phospholipids as a cause of hearing loss for Part 4. Chimeric spike injections seem to have increased autoimmune anti-phospholipid conditions as the Lipid Nanoparticles of the mRNA injections contain phospholipids in their membranes.
Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.
Interesting that this post came when it did…
My wife and I (60 & 61yo) are both “metabolically healthy”. We eat clean, do not drink alcohol, do not take prescription drugs, avoid the sick HC system, build muscle, get quality sleep and sunlight, and take plenty of healthy promoting supplements…And both are unjabbed…
My wife has be having issues with dizziness, vertigo, headaches, and just generally not feel “well”…Like something is not quite right”. She thought it might be an ear infection. The ENT found nothing wrong with her ears and suggested an MRI.
The MRI showed an “old Lacunar infarct in the anterior left corona radiata”.
This probably have a year ago when my wife experience dizziness and needed to be driven home from work.
The only thing we can come up with for all of these symptoms without any reasonable “comorbidities” is the COVID virus/spike protein. 🤷