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.