Chlorzoxazone for sound sensitivity (hyperacusis) and hyper-excitable neural circuits in Fragile X and broader autism – an alternative to Ponstan? Why is Gallic acid beneficial in Autism? Varenicline and other nicotinic therapies, revisited

  

 

Today’s post covers some practical interventions raised recently either in the research, or in the comments section.

 

·         Chlorzoxazone (via Potassium channels – BKCa, SKCa) an old muscle relaxant first approved in 1958

·         Varenicline a drug approved in 2006 that targets nicotinic receptors in the brain

·         Nicotine

·         Tropisetron, an anti-nausea drug that also targets nicotinic receptors in the brain; it was approved in 1992 in Switzerland and is available in the Europe but not the US.

·         Gallic acid, a component of numerous plants/foods (grapes, pomegranates, green tea, red wine etc) that have been used in traditional medicine across different cultures

 

The common link between the first four is the sensory problems usually found across all severities of autism, and some forms of ADHD/autism-lite. It can be either sound sensitivity (hyperacusis) or misophonia (impaired sensory gating), both of which often co-occur in the same person.

We will refer to some of the excellent research into Fragile X syndrome. This is the most common single gene type of autism; most autism is polygenic and some is not of genetic origin at all (hypoxia during birth, sepsis etc).

 

Let’s start with the easiest topic.

 

Gallic acid

I saw the recent study below and wondered what is gallic acid.

 

Vitamin C and Gallic Acid Ameliorate Motor Dysfunction, Cognitive Deficits, and Brain Oxidative Stress in a Valproic Acid‐Induced Model of Autism

Autism, a developmental‐neurodegenerative disorder, often manifests as social communication difficulties and has been correlated to oxidative stress in the brain. Vitamins C and gallic acid (GA) possess potent antioxidant properties, making them potential candidates for addressing autism‐related issues. This study examined the influence of vitamin C (Vit C) and GA on behavioral, motor, and cognitive performance, along with the assessment of brain oxidative markers, using an experimental model of autism.

Finding

The prenatal VPA‐induced autism model increased nociceptive threshold, heightened anxiety‐like behaviors, impaired balance power, delayed spatial learning, elevated malondialdehyde, and decreased glutathione and catalase levels in the brains of the male offspring. Administration of Vit C and GA effectively mitigated these anomalies.

Conclusions

Vit C and GA could potentially alleviate anxiety‐like behaviors, motor and cognitive deficits, and brain oxidative stress markers in a prenatal rat autism model. This underscores their viability as potential pharmacological interventions for treating autistic dysfunction.

 

Gallic acid is a naturally occurring organic acid widely found in various plants, fruits, and foods. It is notable for its antioxidant, anti-inflammatory, and antimicrobial properties, making it of interest in health and medicine.

For no obvious reason, gallic acid has never been commercialized as a supplement, but gallic acid is one of the reasons a glass of red wine a day may well be good for you.  It can give a you a 20 mg dose of gallic acid.

Red wines made from grape varieties with higher tannin content, such as Cabernet Sauvignon or Pinot Noir, tend to have higher levels of gallic acid because tannins contain gallic acid. Longer aging, especially in oak barrels, can increase gallic acid due to the extraction from the wood.

The new study suggests that gallic acid is a potential pharmacological intervention for treating autism.  It joins an already very long list! 

 

Varenicline and other nicotinic therapies

Our reader Dragos in Romania recently asked for help obtaining Varenicline, which is also sold as Chantix. This drug is similar to using a nicotine patch, but different in some important ways.

DAN doctors in the US used to prescribe nicotine patches to children with autism.

There is a lot of research to support the use  of therapies that target a specific nicotinic receptor in the brain called the alpha 7 nicotinic acetylcholine receptor (α7 nAChR).

Nicotine itself activates all nicotinic receptors, not just α7 nAChR.

Dragos want to trial the smoking cessation drug Varenicline, which targets α7 nAChRs and a little bit the one called α4β2 nAChR.

 

α7 nAChRs

These receptors are well known to be implicated in diseases such as Alzheimer's, schizophrenia, autism, and epilepsy.

They affect:

Cognition and memory

·        α7 nAChRs are involved in synaptic plasticity, learning, and memory formation due to their role in calcium signaling and modulation of neurotransmitter release.

·        Highly expressed in the hippocampus, which is critical for memory processing.

Neuroprotection

·        Calcium influx through α7 nAChRs activates signaling pathways that promote cell survival and neuroprotection.

·        Involved in reducing neuroinflammation and protecting against excitotoxicity.

Modulation of Neurotransmitter Release

·        Regulate the release of dopamine, glutamate, GABA, and serotonin, impacting mood, arousal, and reward mechanisms.

Inflammatory Regulation

·        Present on immune cells, where they regulate the release of pro-inflammatory cytokines like TNF-α via the cholinergic anti-inflammatory pathway.

Sensory Gating

·        α7 nAChRs are crucial for sensory filtering, preventing sensory overload. Dysfunction in these receptors is linked to conditions like autism and schizophrenia.

 

α4β2 nAChRs

These play a role in:

Cognitive function

·        Involved in attention, learning, and memory.

·        Enhances synaptic plasticity in brain regions like the hippocampus.

Dopamine release

Pain modulation

Mood regulation

 

Research has shown reduced expression of both α7 nAChRs and α4β2 nAChRs in the brains of people with autism.

Dragos has good reason to trial Varenicline; not only has another young adult in Romania with severe autism recently responded well, but there are published case reports to give further support.

 

Varenicline in Autism: Theory and Case Report of Clinical and Biochemical Changes

Objective: To explore the potential benefits of varenicline (CHANTIX^®), a highly specific partial agonist of neuronal α4β2 nicotinic acetylcholine receptors (nAChR), for autistic symptoms, and present resulting biochemical changes in light of dopamine-related genotype.

Methods: The clinical and biochemical changes exhibited by a 19-year-old severely autistic man following the use of low-dose varenicline in an ABA experiment of nature, and his genotype, were extracted from chart review. Clinical outcome was measured by the Ohio Autism Clinical Impression Scale and 12 relevant urine and saliva metabolites were measured by Neuroscience Laboratory.

Results: With varenicline, this patient improved clinically and autonomic biochemical indicators in saliva and urine normalized, including dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine, norepinephrine, taurine, and histamine levels. In addition, with varenicline, the dopamine D1 receptor (DRD1) antibody titer as well as the percent of baseline calmodulin-dependent protein kinase II (CaM KII) activity dropped significantly. When varenicline stopped, he deteriorated; when it was resumed, he again improved. Doses of 0.5, 1, and 2 mg daily were tried before settling on a dose of 1.5 mg daily. He has remained on varenicline for over a year with no noticeable side effects.

Conclusion: This report is, to the best of our knowledge, only the second to demonstrate positive effects of varenicline in autism, the first to show it in a severe case, and the first to show normalization of biochemical parameters related to genotype. As with the previous report, these encouraging results warrant further controlled research before clinical recommendations can be made.

 

Varenicline vs Nicotine 

Let’s compare the mechanisms of action:

Varenicline

• Partial agonist at the α4β2 nicotinic acetylcholine receptor (nAChR) and a full agonist at α7 nAChRs.
• Modulates neurotransmitter release (e.g., dopamine, glutamate), which may improve cognitive function and reduce repetitive behaviors in ASD.
• FDA-approved for smoking cessation.

 

Nicotine Patches

• Deliver nicotine, a full agonist at nAChRs.
• Broadly activate multiple nAChR subtypes, leading to enhanced cholinergic signaling.
• Typically used for smoking cessation

 

Other Considerations

Varenicline

·         Offers more targeted modulation of nAChRs with less widespread cholinergic activation.

• Varenicline’s mechanism prevents full desensitization, maintaining its effects over time.

·         May be preferred if minimizing side effects like overstimulation is important.

 

Nicotine Patches:

• Easy to administer and widely available but less specific in its action, which may lead to more off-target effects.
• Nicotine can lead to rapid receptor desensitization and tolerance, especially with continuous delivery via patches.

 

Alternatives

There are some theoretical alternatives, such as:

 

ABT-126 (Pozanicline)

·         Type: Selective α7 nAChR agonist.

·         Status: Investigated for Alzheimer's disease and schizophrenia.

·         Cognitive enhancement and improved sensory gating.

 

RG3487 (MEM 3454)

·         Type: Partial α7 nAChR agonist and modulator of glutamate receptors.

·         Status: Investigated for schizophrenia and cognitive impairment.

·      Improves cognition and reduces symptoms like sensory gating deficits.

 

The one that caught my attention previously when writing about this subject was Tropisetron.

 

Tropisetron:

• Already approved as an antiemetic but also acts as a weak α7 nAChR agonist.
• Potential benefits in cognitive and inflammatory disorders.

 

Clinical Evidence with Tropisetron

Schizophrenia

Early studies show cognitive and sensory gating improvements in schizophrenia patients treated with tropisetron.

One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia

Not to forget Vagus Nerve Stimulation (VNS)

The vagus nerve activates α7 nAChRs on immune cells, reducing inflammation without immunosuppression.

The vagus nerve indirectly affects α7 and α4β2 nAChRs in the brain by modulating acetylcholine release.

Vagus nerve stimulation is already used in epilepsy, depression, and inflammatory disorders.

 

It is worthwhile highlighting the effect on people with some types of GI disorder. There is a known association between Asperger’s and ulcerative colitis.

 

Nicotine and Ulcerative Colitis (UC)

·         Smoking appears to have a protective effect on ulcerative colitis.

·         Smokers are less likely to develop UC, and those who quit smoking are at higher risk of developing the condition.

·         Current smokers with UC may experience milder disease with fewer flares and less severe symptoms.

The suggested mechanism

·         Dysregulated inflammation in the colonic mucosa leads to ulcerations, diarrhea, and abdominal pain.

·         α7 nAChR activation may reduce this inflammation, aiding in mucosal healing and symptom improvement.

·         Nicotine’s anti-inflammatory effects may play a role by modulating cytokine release (e.g., reduced IL-8 and TNF-α).

·         Nicotine also stimulates mucus production and increases colonic blood flow, potentially improving mucosal healing.

·         Smoking-induced changes in the microbiome may also reduce UC severity.

 

Note that for Crohn's Disease (CD) and Irritable Bowel Syndrome (IBS) smoking makes the symptoms worse.

 

So, it would make sense to use vagal nerve stimulation for inflammatory bowel disease?

 

Here are results from 2023

 

Vagus nerve stimulation reduces inflammation in children with inflammatory bowel disease

 

Bioelectronic medicine researchers at The Feinstein Institutes for Medical Research and Cohen Children’s Medical Center published results today, in the journal Bioelectronic Medicine, from a proof-of-concept clinical trial that showed non-invasive, non-pharmacological transcutaneous auricular vagus nerve stimulation (ta-VNS), or stimulating in the ear, significantly reduced inflammation in more than 64 percent of pediatric patients with IBD. 

Dr. Sahn and his team used a commercially available transcutaneous electrical nerve stimulator (TENS) unit (TENS 7000) and sensor probe for the trial. Two earbuds on the probes were placed on a small area of the external ear called the cymba conchae, where the vagus nerve is most accessible. For five-minute intervals, the patients received the stimulation for a total of 16 weeks.

 Finally to BKCa and SKCa channels in Fragile X syndrome (FXS) and broader autism !

 

Let’s have a quick recap on Fragile X.

 

Fragile-X

Fragile X (FXS) is the most common single gene cause of intellectual disability (IQ less than 70).

FXS affects approximately 1 in 4,000 males and 1 in 8,000 females.

The condition is very well studied and the Fragile X gene (FMR1) is considered an autism gene.

I am surprised how rarely (never?) FXS parents comment in this blog. They are actually the ones who stand to benefit the most, given how well-studied their syndrome is and how many treatment options exist. I was recently discussing this exact point with an autism therapist with an FXS patient – why do parents remain passive and not react?

 

More severe in males than females

Males have one copy of the FMR1 gene, while females have two.

In females with the full mutation, symptoms are generally less severe than in males due to what is called random X-inactivation. Since females have two X chromosomes, one of the X chromosomes in each cell is randomly inactivated. In cells where the X with the mutation is inactivated, FMRP is produced normally, and in cells where the normal X is inactivated, no FMRP is produced. The severity of symptoms often correlates with the proportion of cells in which the mutated X is active.

In a strange twist of fate females with the milder form of FXS, called premutation, have the greatest chance of being infertile. This is due to Fragile X-associated primary ovarian insufficiency (FXPOI).

 

Testing

The ability to conduct genetic testing began in the 1990s, became more widespread by the mid-1990s, and became integrated into routine clinical practice in the early 2000s. Today, genetic testing for Fragile X is a standard tool used to diagnose FXS, assess carrier status, and inform genetic counselling.

You can also identify Fragile X based on facial features and this is a common practice, especially in the early diagnosis of individuals with the syndrome.

BKCa and SKCa channels in autism and Fragile X

Ion channel dysfunctions play a key role in all neurological conditions. A great deal is known about them, making them an excellent target for intervention.

Fragile X is such a well-studied condition that you can access all the information very easily.

For other single gene autisms and the more common idiopathic (unknown cause) autism it is more a matter of guesswork. 

This recent paper is excellent: 

Channelopathies in fragile X syndrome

The paper lists all the proven ion channel dysfunctions and suggests how to treat some of them.

Potassium channels – BKCa, SKCa, Kv1.2, Kv3.1, Kv4.2,

Calcium channels – Cav1.3, Cav2.1, Cav2.3,

Misc – HCN, NKCC1, AMPAR, NMDAR, GABA_AR

 

Targeting BKCa, SKCa in Fragile X and for hyperacusis in broader autism

In FXS, hyperexcitability in brain circuits is thought to contribute to cognitive and behavioral symptoms.

Preclinical studies suggest that SKCa and BKCa channel activators may correct this hyperexcitability and improve neural network function.

The therapeutic effects of a cheap drug called chlorzoxazone in FXS models are believed to stem from its ability to enhance BKCa channel activity. These channels play a pivotal role in regulating neuronal firing rates and neurotransmitter release. By activating BKCa channels, chlorzoxazone may counteract the neuronal hyperexcitability observed in FXS, leading to improved behavioral and sensory outcomes.

BKCa channels are indispensable for hearing, as they regulate frequency tuning, temporal precision, and signal transmission in both cochlear hair cells and auditory neurons. Dysfunctions in these channels are linked to hearing impairments like frequency discrimination deficits, tinnitus, and hyperacusis (sound sensitivity). Modulating BKCa activity offers a promising avenue for treating auditory disorders.

 

Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and autistic-like symptoms such as social deficits. Despite considerable efforts, effective pharmacological treatments are still lacking, prompting the need for exploring the therapeutic value of existing drugs beyond their original approved use. One such repurposed drug is chlorzoxazone which is classified as a large-conductance calcium-dependent potassium (BKCa) channel opener. Reduced BKCa channel functionality has been reported in FXS patients, suggesting that molecules activating these channels could serve as promising treatments for this syndrome. Here, we sought to characterize the therapeutic potential of chlorzoxazone using the Fmr1-KO mouse model of FXS which recapitulates the main phenotypes of FXS, including BKCa channel alterations. Chlorzoxazone, administered either acutely or chronically, rescued hyperactivity and acoustic hyper-responsiveness as well as impaired social interactions exhibited by Fmr1-KO mice. Chlorzoxazone was more efficacious in alleviating these phenotypes than gaboxadol and metformin, two repurposed treatments for FXS that do not target BKCa channels. Systemic administration of chlorzoxazone modulated the neuronal activity-dependent gene c-fos in selected brain areas of Fmr1-KO mice, corrected aberrant hippocampal dendritic spines, and was able to rescue impaired BKCa currents recorded from hippocampal and cortical neurons of these mutants. Collectively, these findings provide further preclinical support for BKCa channels as a valuable therapeutic target for treating FXS and encourage the repurposing of chlorzoxazone for clinical applications in FXS and other related neurodevelopmental diseases.

  

·        Chlorzoxazone

In the FXS research they repurpose a drug called chlorzoxazone to activate BKCa channels, with positive results

 

·        Mefenamic acid (Ponstan)

In this blog Ponstan has shown promise to treat hyperacusis. Ponstan is a known activator of both BKCa and SKCa channels.

 

Which is “better” chlorzoxazone or Ponstan?

According to the science chlorzoxazone is more potent than Ponstan in affecting both BKCa and SKCa channels.

Ponstan has more effects on Kv channels like Kv7. Kv7 is implicated in autism and epilepsy.

In terms of gene expression Ponstan has more direct effects on gene expression due to its modulation of inflammatory pathways and inhibition of prostaglandin synthesis.

Chlorzoxazone primarily acts on ion channels, and its effects on gene expression are secondary and less pronounced.

In conclusion the two drugs are very different, both potentially useful, and some of their actions, such as on hyperacusis, are overlapping.

  

Conclusion

Chlorzoxazone an inexpensive drug used to treat muscle spasms is also known for its effects on calcium-activated potassium channels (BKCa and SKCa).

Some claim that Chlorzoxazone may affect GABAa and/or GABAb receptors, but that appears not to be the case.

The research suggests that Chlorzoxazone should have a beneficial effect in FXS and very likely would have a benefit in some broader autism and in hyperacusis specifically.

The effects of Chlorzoxazone are likely to overlap with the effects of Ponstan. Ponstan is quite possibly also going to be effective in FXS, as it is in broader autism.

There are many suggested therapies for FXS (Metformin, Lovastatin, Baclofen, Acamprosate, Gabapentin, Minocycline, Memantine, Rapamycin, L-carnitine, Omega 3 etc). None, when taken alone, are game-changers.

Every parent of a child with Fragile X should read the paper I have linked to in this post.

 

Channelopathies in fragile X syndrome

 

It is full of excellent ideas. If NKCC1 is overexpressed, as is suggested, trial bumetanide.

As in all autism, polytherapy is going to be key. No single therapy can be highly effective with so many dysfunctions present. To quote from the above paper:-

 “Ultimately, the most effective treatment strategies are likely to be multifactorial.”

This means do not be surprised if you need 5 different drugs, with 5 different targets to produce a game-changing effect. Better 5 cheap old re-purposed generic drugs than a single brand-new drug with little overall effect and that costs a king’s ransom, each and every year.

Unfortunately, a personalized approach will need to be used to find such a polytherapy. What works at one age may not be beneficial at another age. Even within single gene autisms, treatment response can vary widely from person to person.

At a conference, I did ask a clinician who is an “expert” in Fragile X, does she apply any of the existing therapies from the research, to her patients. She was rather taken aback by the idea and said “no, we have to follow the protocols.” So, an expert in exactly what then? An expert would make the protocols, if none existed.

The therapeutic effects of apigenin are pleiotropic. Is its effect on sound sensitivity mediated via potassium channels?

Chamomile, a good source of Apigenin

 

Today we return to flavonoids, those healthy chemicals found in fruits, vegetables, flowers etc.

In particular, the focus is on apigenin, found in things like chamomile, parsley, oregano and in medicinal herbs like Bacopa monnieri.

 

Why the interest in Apigenin?

I did discover a while back that sound sensitivity in some autism responds almost immediately to low dose Ponstan (Mefenamic acid), which is a widely used as a pain reliever.

I was recently informed by a reader who responds well to Ponstan (250mg once a day) that he gets exactly the same relief from sound sensitivity from taking the flavonoid Apigenin (500mg a day). 

Both Ponstan and Apigenin are OTC in many countries. In countries like Greece Ponstan is extremely cheap.  In the US Ponstan is very expensive and supplements tend to be cheap. 

For adults with sound sensitivity drinking chamomile tea might be a good source of 50 mg of Apigenin (you would need about 20g of chamomile flowers). Using the dried flowers likely gives better results than ready-made tea bags.

 

Pleiotropic effects

Both Ponstan and apigenin have numerous beneficial effects.  I noted in my earlier posts on Ponstan that it seems to offer protection from Alzheimer’s. Perhaps surprisingly, people who take Ponstan are much less likely to develop Alzheimer’s. Nobody has studied apigenin in human Alzheimer’s, but in animal studies, apigenin has been shown to improve cognitive function, reduce amyloid plaques, and protect neurons from damage.

 

Other Flavonoids used in Autism

Dr Theoharides wrote a lot about flavonoids to treat autism and mast cell disorders.  His product Neuroprotek is a combination of three flavonoids: luteolin, quercetin, and rutin, which are found in plants such as celery, onions, and citrus fruits.

Epigallocatechin gallate (EGCG) is a flavonoid found in green tea. The Spanish like doing research on EGCG and they believe it has promise as an autism therapy. One of the effects is to modify the gut microbiome. EGCG has also been shown to accumulates in mitochondria making it an interesting therapeutic candidate for neurodegenerative diseases involving neuronal apoptosis triggered by mitochondrial oxidative stress. It has been studied in Down syndrome, Rett syndrome and some other models of autism.

 

A very detailed overview is available in the paper below:-

The Emerging Role of Flavonoids in Autism Spectrum Disorder: A Systematic Review

Although autism spectrum disorder (ASD) is a multifaceted neurodevelopmental syndrome, accumulating evidence indicates that oxidative stress and inflammation are common features of ASD. Flavonoids, one of the largest and best-investigated classes of plant-derived compounds, are known to exert antioxidant, anti-inflammatory, and neuroprotective effects. This review used a systematic search process to assess the available evidence on the effect of flavonoids on ASD. A comprehensive literature search was carried out in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. A total of 17 preclinical studies and 4 clinical investigations met our inclusion criteria and were included in the final review. Most findings from animal studies suggest that treatment with flavonoids improves oxidative stress parameters, reduces inflammatory mediators, and promotes pro-neurogenic effects. These studies also showed that flavonoids ameliorate the core symptoms of ASD, such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination. However, there are no randomized placebo-controlled trials that support the clinical efficacy of flavonoids in ASD. We only found open-label studies and case reports/series, using only two flavonoids such as luteolin and quercetin. These preliminary clinical studies indicate that flavonoid administration may improve specific behavioral symptoms of ASD. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of flavonoids on features of ASD. These promising preliminary results may provide the rationale for future randomized controlled trials aimed at confirming these outcomes.

 

It seems that the many flavonoids have numerous beneficial effects - this is why it is important to include them in your diet.

 

Sytrinol

Years ago, I wrote about Sytrinol, a dietary supplement that is made from citrus peel extract. It contains polymethoxylated flavones (PMFs), which are a type of flavonoid. It mainly contains nobiletin and tangeritin, flavones that are found in citrus fruits, such as lemons, oranges, and grapefruits. They have been shown to have a number of health benefits, including lowering cholesterol, reducing inflammation, and protecting cells from damage.

The idea was of interest because these flavones are known to activate PPAR-gamma, which seemed potentially beneficial in autism.  Readers did confirm Sytrinol provided a cognitive benefit, but it only lasts a few days and is then lost.

 

Sources of Apigenin

Apigenin is sold as a supplement.

Chamomile is one of the oldest, most widely used and well documented medicinal plants in the world and has been recommended for a variety of healing applications for centuries. Apigenin is thought to be one of the most potent substances found within it.

Bacopa monnieri is another rich source of flavonoids being a good source of luteolin and apigenin. An extract of Bacopa monnieri, a nootropic herb, has been used to evaluate its neuroprotective effect in a valproic acid (VPA) model of ASD. The results showed that B. monnieri extract may attenuate VPA-induced damage by restoring antioxidant enzymes and reducing inflammatory cytokines in the hippocampus and prefrontal cortex.

 

The biological effects of Apigenin

 What does the Google AI (artificial intelligence) program Bard have to say:-

 

Apigenin is a flavonoid that is found in a variety of plants, including chamomile, parsley, celery, and citrus fruits. It has several potential health benefits, including:

Antioxidant. Apigenin is an antioxidant, which means it can help protect cells from damage caused by free radicals. Free radicals are unstable molecules that can damage DNA, proteins, and other cellular structures.

Anti-inflammatory. Apigenin has anti-inflammatory properties, which can help reduce inflammation in the body. Inflammation is a contributing factor to many diseases, including heart disease, cancer, and arthritis.

Cancer prevention. Apigenin has been shown to have cancer-fighting properties in both animal and human studies. It may help prevent cancer by blocking the growth and spread of cancer cells.

Brain health. Apigenin may be beneficial for brain health. It has been shown to improve cognitive function in animal studies, and it may also help protect against Alzheimer's disease and other neurodegenerative diseases.

Heart health. Apigenin may help improve heart health. It has been shown to lower blood pressure and cholesterol levels, and it may also help protect against heart arrhythmias.

Hormone modulation. Apigenin may modulate the production of hormones, such as estrogen and testosterone. This could have benefits for women's health, such as reducing the risk of breast cancer and improving menopausal symptoms.

Immune health. Apigenin may boost the immune system. It has been shown to increase the production of white blood cells, which help fight infection.

Other benefits. Apigenin may also have other health benefits, such as relieving anxiety, promoting sleep, and strengthening bones.

When you push Bard a little bit you get more:

Apigenin and ion channels, Bard?

Apigenin is a flavonoid that has been shown to interact with a variety of ion channels in the body. These include:

Voltage-gated calcium channels. Apigenin has been shown to inhibit the activity of voltage-gated calcium channels, which are involved in the regulation of many cellular processes, including muscle contraction, cell growth, and cell death.

Transient receptor potential vanilloid 4 (TRPV4) channels. TRPV4 channels are activated by heat and inflammation, and they play a role in pain perception, thermoregulation, and inflammation. Apigenin has been shown to activate TRPV4 channels, which could have potential implications for the treatment of pain and inflammation.

Nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels that are activated by acetylcholine. They are involved in a variety of functions, including learning, memory, and muscle contraction. Apigenin has been shown to potentiate the activity of nAChRs, which could have potential implications for the treatment of Alzheimer's disease and other neurodegenerative diseases.

Potassium channels: Potassium channels are responsible for the efflux of potassium ions from cells. Apigenin has been shown to activate some types of potassium channels, which can have cardioprotective effects.

Gamma-aminobutyric acid (GABA)A receptors. GABAA receptors are ligand-gated ion channels that are activated by GABA. They are involved in the regulation of anxiety, sleep, and epilepsy. Apigenin has been shown to modulate the activity of GABAA receptors, which could have potential implications for the treatment of anxiety and epilepsy.

 

Which potassium channels, Bard? 

Apigenin has been shown to activate some types of potassium channels, including:

Small conductance calcium-activated potassium channels (SK channels): SK channels are activated by calcium ions and play a role in regulating cell excitability. Apigenin has been shown to activate SK channels in a number of cell types, including neurons, smooth muscle cells, and cardiac cells.

Large conductance calcium-activated potassium channels (BK channels): BK channels are also activated by calcium ions and play a role in regulating cell excitability and blood pressure. Apigenin has been shown to activate BK channels in some cell types, but the effects are less well-studied than the effects on SK channels.

Transient receptor potential vanilloid 4 (TRPV4) channels: TRPV4 channels are activated by a variety of stimuli, including heat, inflammation, and mechanical stress. Apigenin has been shown to activate TRPV4 channels in some cell types, but the effects are less well-studied than the effects on SK and BK channels.

 

The effect of mefenamic acid on potassium channels, Bard? 

Mefenamic acid has been shown to have effects on a variety of ion channels, including potassium channels.

In vitro studies have shown that mefenamic acid can activate certain types of potassium channels, such as small conductance calcium-activated potassium channels (SK channels) and large conductance calcium-activated potassium channels (BK channels). This activation of potassium channels can lead to a decrease in the excitability of cells, which can be beneficial in conditions where excessive cell excitability is a problem, such as epilepsy and arrhythmias.

 However, mefenamic acid can also inhibit certain types of potassium channels, such as ATP-sensitive potassium channels (KATP channels). This inhibition of KATP channels can lead to an increase in the excitability of cells, which can be harmful in conditions where excessive cell excitability is a problem, such as heart arrhythmias.

The effects of mefenamic acid on potassium channels are complex and depend on the type of channel, the concentration of mefenamic acid, and the cell type. More research is needed to fully understand the mechanisms by which mefenamic acid interacts with potassium channels and the implications for its potential therapeutic applications.

 

Apigenin in Down syndrome

 

Plant Compound Apigenin Reduces Cognitive Deficits in Mouse Model of Down Syndrome

Mice treated with apigenin had better memory and developmental milestone scores.

The plant compound apigenin improved the cognitive and memory deficits usually seen in a mouse model of Down syndrome, according to a study by researchers at the National Institutes of Health and other institutions.

Apigenin is found in chamomile flowers, parsley, celery, peppermint, and citrus fruits. The researchers fed the compound to pregnant mice carrying fetuses with Down syndrome characteristics and then to the animals after they were born and as they matured.

The findings raise the possibility that a treatment to lessen the cognitive deficits seen in Down syndrome could one day be offered to pregnant women whose fetuses have been diagnosed with Down syndrome through prenatal testing. The study appears in the American Journal of Human Genetics.

Down syndrome is a set of symptoms resulting from an extra copy or piece of chromosome 21. The intellectual and developmental disabilities accompanying the condition are believed to result from decreased brain growth caused by increased inflammation in the fetal brain.

Apigenin is not known to have any toxic effects, and previous studies have indicated that it is an antioxidant that reduces inflammation. Unlike many compounds, it is absorbed through the placenta and the blood brain barrier, the cellular layer that prevents potentially harmful substances from entering the brain.

Compared to mice with Down symptoms whose mothers were not fed apigenin, those exposed to the compound showed improvements in tests of developmental milestones and had improvements in spatial and olfactory memory. Tests of gene activity and protein levels showed the apigenin-treated mice had less inflammation and increased blood vessel and nervous system growth.

 

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.

 

Conclusion 

I am still delighted to have found a treatment for my son’s sound sensitivity, which got much more extreme almost overnight a couple of years ago.

I had already established long ago that he got short term sound sensitivity relief from taking a potassium supplement.  Some readers found a potassium supplement provided long term relief.

I thought that Ponstan might provide a good longer term solution and indeed it worked from the first pill.  This low dose therapy also works for other people with sound sensitivity, even one adult who has no autism.  The effective adult dose is 250 mg once a day.

Unlike other fenamate class drugs, like Diclofenac, Ponstan seems to be free from GI side effects at this low dose in most people.

Apigenin is an interesting alternative for those who do not tolerate Ponstan well, or who cannot access it.

A common link between what seems to improve sound sensitivity:

•                    Oral potassium

•                    Ponstan (Mefenamic acid)

•                    Apigenin

is potassium ion channels. 

If you ask Google’s AI program Bard, he will tell you:

“It is possible that all 3 substances could affect the same potassium ion channel in some cell types, but this has not been definitively shown. More research is needed to fully understand the effects of these substances on potassium ion channels.”

Technically Bard is genderless, but he is a reflection of the programmers behind the software. In our house he is called Bart anyway.

Bart does make mistakes, contradicts himself in the same answer and he gives you different answers if you ask the same question more than once. He is also prone to mixing things up, just like humans do.