MS, the gut, and Autism in males and females

 

There is quite a lot in this blog about MS (multiple sclerosis) because it is the classic myelin disorder and so is well researched. Many other neurological conditions, including some autism, also feature impaired myelination. 

One of the very cheap myelin therapies is the old anti-histamine drug Clemastine. I learnt this week that it will be trialed in children with Pitt Hopkins syndrome. It is a very logical choice and some parents have already trialed it. I used it for a few years and did feel there was a benefit. The key is to keep the dose low enough not to cause drowsiness. Very long term use may reduce acetylcholine in the brain, so it is not a forever medicine.

Then I saw some interesting research from Japan showing that it appears that multiple sclerosis starts in the gut.

We already know from interesting US research that you must have had the Epstein-Barr virus (EBV) to be able to develop MS. It also depends on the age at which you caught the virus. The older you were, the bigger the risk of later developing MS. So it is best to get EBV very young, or avoid it entirely by vaccination (expected to be available in 10 years). EBV is also known to increase the risk of certain cancers, so I guess the vaccination will get adopted.

 

The role of the gut

For years, researchers have suspected that the gut plays an important role in neurological conditions. What has been missing is a clear explanation, a step-by-step account of how something happening in the intestine could influence the brain.

A recent study provides exactly that for Multiple Sclerosis.

 

How Intestinal Cells Trigger Multiple Sclerosis

Summary: For years, scientists have suspected that the gut plays a role in Multiple Sclerosis (MS), but the “smoking gun” linking the two has been elusive. A landmark study has finally identified the cellular mechanism: Intestinal Epithelial Cells (IECs)—the cells lining your gut—are acting as “accidental” messengers.

The study found that in patients with MS, these gut cells abnormally express MHC II, a protein that “presents” antigens to the immune system. This interaction mistakenly transforms ordinary immune cells into pathogenic Th17 cells, which then migrate from the gut directly to the central nervous system to attack the brain and spinal cord.

Key Facts

·         The Accidental Messenger: IECs do not normally “talk” to the immune system in this way. In MS, they begin expressing MHC II, which “primes” CD4+ T cells to become aggressive.

·         The Th17 Migration: Using “Kaede” protein tracking (which changes colour under light), researchers proved that these gut-primed Th17 cells physically travel from the intestine to the spinal cord to drive neuroinflammation.

·         Human Connection: The team used single-cell RNA sequencing on human biopsies to confirm that the same inflammatory patterns seen in mouse models are present in the intestines of human MS patients.

·         New Treatment Target: Most current MS therapies target B cells in the blood; this study suggests that treating the gut environment or blocking the antigen-presenting activity of gut cells could stop MS at its source.

 

This new knowledge should shift the focus of treatment away from simply suppressing the immune system after damage has started, toward stopping the problem earlier at its source. Future therapies may aim to block these abnormal gut signals, target specific inflammatory pathways, and use gut-focused treatments such as microbiome modulation and diet. Overall, the goal is to prevent the immune system from being mis-trained in the first place, rather than just managing the consequences later.

  

The actual study:-

Intestinal epithelial MHC class II induces encephalitogenic CD4 T cells and initiates central nervous system autoimmunity

The gut as an immune training ground

The key finding is that cells lining the gut, intestinal epithelial cells, can act as unexpected immune instructors.

In MS, these cells begin expressing MHC class II, a molecule normally used by immune cells to “present” antigens. This abnormal behavior turns the gut lining into a kind of misguided training center.

The result is:

• Activation of Th17 cells
• These cells become highly inflammatory
• They migrate from the gut to the brain and spinal cord
• They drive autoimmune attack on myelin

This is a causal pathway from gut to brain.

 

A shared biological axis

The gut is not just influencing the brain, it is actively programming immune cells that control it.

This gut-immune-brain axis likely operates across multiple conditions, including autism, asthma, and ADHD.

 

Intestinal epithelial cells and autism

Intestinal epithelial cells sit at the center of the gut–immune interface and may also play a role in Autism.

They have three key functions.

 

1. Barrier control

IECs regulate what passes from the gut into the body.

If this barrier is altered, microbial products and metabolites may enter circulation and immune activation may increase

Some studies in autism report increased gut permeability, suggesting altered epithelial function.

 

2. Immune signaling

IECs actively communicate with the immune system. They release cytokines, influence T-cell behavior and potentially affect pathways like Th17 cells

In MS, abnormal IEC signaling directly drives inflammation.

In autism, similar immune pathways are implicated, though less directly established.

 

3. Microbiome interpretation

IECs “read” signals from gut microbes.

·        balanced microbiome produces healthy regulatory signals

·        dysbiosis produces inflammatory signals

 

In autism, microbiome differences are common, meaning IEC signaling may be altered.

 

Autism - same axis, different outcome

In autism, we see:

• altered microbiome
• gut inflammation
• immune activation (including Th17/IL-17 in some cases)

 

The difference is timing and target.

 

Step	MS (Adult)	Autism (Early Life)
Gut signal	IEC activation	Dysbiosis / gut inflammation
Immune response	Pathogenic Th17 cells	Altered immune signaling
Brain effect	Myelin attack	Developmental disruption
Timing	Adulthood	Early childhood

 

Why more females have MS

Multiple Sclerosis is 2–4 times more common in females.

Females have:

• stronger immune responses
• two X chromosomes (more immune genes)
• greater responsiveness to immune signals

When the gut sends the wrong signal, females are more likely to amplify it into autoimmunity.

Hormonal shifts (e.g., pregnancy/postpartum) further support an immune-driven mechanism.

 

Why more males have Autism

Severe autism is 3–4 times more common in males.

Males show:

• higher vulnerability during early brain development
• only one X chromosome (less genetic backup)
• less regulated early-life immune signaling

When the gut–immune system is activated early, males are more likely to cross the threshold into neurodevelopmental disruption.

Females appear more protected via:

• neural resilience
• better early immune regulation
• genetic redundancy

 

The EBV connection: a required trigger

One of the most important recent discoveries is the role of Epstein-Barr Virus infection in MS.

Large longitudinal studies show:

• individuals not infected with EBV almost never develop MS
• after EBV infection, the risk of MS increases dramatically (around 30-fold)

This suggests EBV is a necessary but not sufficient factor.

 

How EBV fits the model

EBV infects and persists in B cells, altering immune behavior. It may:

• create immune cells that recognize both viral proteins and brain proteins (molecular mimicry)
• keep B cells chronically activated
• prime the immune system toward autoimmunity

 

A multi-hit model of MS

The emerging picture is that MS requires multiple aligned factors:

1.     EBV infection
creates autoreactive immune potential

2.     Gut immune dysregulation
generates inflammatory Th17 cells

3.     Environmental modifiers (e.g., low vitamin D)
reduce immune regulation

Together, these drive immune attack on the brain

EBV loads the gun, the gut pulls the trigger, and the immune system fires at the brain.

 

Why MS varies by latitude

MS prevalence increases with distance from the equator.

• Lower rates near the equator
• Higher rates in northern regions

This reflects environmental effects on immune regulation.

 

Vitamin D and sunlight

Reduced sunlight lowers vitamin D, which normally:

• suppresses excessive Th17 cells activity
• promotes immune tolerance

Low vitamin D removes a key brake on autoimmunity.

 

Infection timing

Epstein-Barr Virus infection often occurs later in higher latitude regions, triggering stronger immune responses.

 

Microbiome differences

Geography affects diet and microbial exposure, shaping the gut–immune axis.

 

Hygiene effects

Reduced early microbial exposure may impair immune training.

 

Why some conditions improve with age

A striking observation across medicine is that many children “grow out of” certain conditions.

This includes:

• Mild autism (in some cases)
• Asthma
• Attention Deficit Hyperactivity Disorder

This reflects a shared biological pattern.

 

The dynamic regulation model

Early life is a period of high instability:

• the gut barrier is still developing
• the microbiome is fluctuating
• the immune system is learning tolerance
• the brain is highly sensitive

This creates a system that is:

• more reactive
• more inflammatory
• more vulnerable

 

What Changes Over Time

Three stabilizing processes occur:

1. Gut stabilization

• microbiome becomes more consistent
• fewer abnormal immune triggers

2. Immune regulation improves

• better control of inflammation
• reduced overactivation (including Th17 pathways)

3. Brain maturation

• circuits strengthen
• compensatory pathways develop
• regulation improves

 

The threshold effect

Symptoms can be viewed as crossing a threshold:

• Above threshold → visible condition
• Below threshold → mild or no symptoms

As stability improves:

• inflammation ↓
• regulation ↑

The individual may drop below the clinical threshold (unless they keep lowering the diagnostic threshold, as with autism)

 

Implications for Treatment

Focus on stabilizing the system, not just suppressing symptoms.

Potential approaches:

• improve gut health and microbiome stability
• reduce inappropriate immune activation
• support metabolic resilience
• ensure adequate vitamin D and environmental exposure
• minimize chronic inflammatory triggers

 

For MS:

• targeting EBV and gut immune programming may prevent disease at its source

 

For autism and related conditions:

• early stabilization of the gut–immune axis may improve outcomes

 

Does severe autism improve with age?

Severe autism is not a fixed condition where everything is determined at the start of life. While some children begin with greater challenges than others, what happens over time depends heavily on how skills develop during the long period of childhood and adolescence. These include communication, social interaction, emotional regulation, and daily living abilities. Early progress in these areas can create a positive ripple effect, making future learning easier and more natural.

If certain skills are delayed or missed early on, development may be slower—but this does not mean progress is impossible. The brain remains capable of learning and adapting, even later in life. This means that outcomes are not set in stone, much is up to the parents.

What shapes these outcomes is a combination of factors. Biology plays an important role—things like brain plasticity, energy levels, and overall health can influence how easily a child can learn. Biology can be modified pharmacologically, which is what EpiphanyASD is all about.

Biology is only part of the picture. Therapy, education, and the home environment are equally important. Structured teaching, repetition, encouragement, and meaningful interaction all create opportunities for skills to develop.

Importantly, these factors interact with each other. When a child’s biological state improves, they become more receptive to learning. In turn, effective therapy and support can help build new abilities, which further improves confidence, behavior, and engagement. This creates a positive cycle where progress builds on progress. Nothing changes over night, it is a slow process. Increasing skill acquisition rate by just 10% can lead to a massive difference over a decade.

This is why outcomes in autism are so variable. Two children who start at a similar level can follow very different paths depending on the opportunities they have and how their abilities are supported over time.

There are also important developmental windows, particularly in early childhood, when learning certain skills is easier. However, these windows do not fully close. Progress may become slower later, but it is still very much possible. Many individuals continue to gain skills well into adolescence and adulthood.

In this way, severe autism is better understood as a dynamic developmental process rather than a fixed outcome. The trajectory can be changed, sometimes substantially, depending on how biology, learning, and environment come together over time.

 

A note on EBV

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is a common virus that infects most people and remains in the body for life. It is best known for causing infectious mononucleosis (“glandular fever”), especially when infection occurs in adolescence.

EBV spreads via saliva.

Childhood transmission is very common globally, but as hygiene increases it gets caught at older ages. In western countries kissing during adolescence is a major route.

90-95% of adults carry the EBV, the only question is at what age they were exposed.

Early exposure to EBV is less risky than late exposure. This fits the hygiene hypothesis, which has been covered in this blog and my book.

The hygiene hypothesis proposes that reduced exposure to microbes in early life results in less “training” of the immune system and causes higher risk of immune dysregulation in later life.

Exposure to pets at home will help train a young child’s immune system, but does not expose him/her to EBV, which is exclusively a human virus. 

Applying insights from novel Alzheimer’s treatments to autism – mast cell stabilizers, brain cholesterol reduction, menthol, and vitamin D

 

Treating autism has many parallels with treating other complex neurological conditions like dementia or MS. You need to treat multiple individual features of the disease and then you will the greatest effect, this is called polytherapy.

·        Mast cell activation is a common feature in both autism and Alzheimer’s.

·        Neuroinflammation is a fundamental part of autism and Alzheimer’s. It looks like both menthol and vitamin D may have a role to play.

·        Impaired cholesterol metabolism in the brain is a key feature of Alzheimer’s and occurs in some autism. It can be either too much, or too little. 

An interesting new idea in Alzheimer’s research is to use a potent mast cell stabilizer called Masitinib. It is interesting because this drug has already been commercialized to treat pets.

 

Masivet UK (Kinavet US) Cancer Treatment Tablets for Dogs

 

There is great deal in this blog about mast cells and autism.

Many readers give their child cromolyn sodium, which is an excellent mast cell stabilizer, but it poorly crosses the blood brain barrier. While cromolyn sodium is effective for conditions where mast cell activity is predominantly peripheral, its limited CNS action makes it less suitable for addressing neuroimmune dysregulation in autism, or other brain-related conditions.

Ketotifen is another mast cell stabilizer and it does cross the blood brain barrier better. It has also been widely used in autism. It is cheap in some countries but expensive in others.

One known feature of mast cell activation is an impaired blood brain barrier (BBB), so some of these drugs may be more effective than expected.

Studies suggest that masitinib can cross the BBB, particularly in conditions where the BBB is disrupted (inflammation, neurodegenerative diseases, or neuroimmune disorders).

Masitinib works by inhibiting tyrosine kinases  involved in mast cell activation and degranulation. By reducing mast cell activity, it may help to mitigate neuroinflammatory processes implicated in conditions like autism, Alzheimer's disease, and indeed multiple sclerosis (MS).

For those that want an up to date summary of mast cell activation in autism there is an excellent new paper.

 

The role of mast cells (MCs) in Autism Spectrum Disorder

 

Highlights

·        Increased MC activity may be linked to the development of ASD.

·        MC mediators influence neuroinflammatory pathways that are altered in ASD.

·        MCs can interact with other immune and neuronal cells contributing to ASD symptoms.

·        The role of MC in gut permeability and microbiota dysbiosis may also underly gastrointestinal comorbidities in ASD.

·        Targeting MC activity offers promising therapeutic avenues in treatment of ASD.

 

ASD represents a multifaceted condition influenced by genetic, environmental, and immune-related factors. MCs have emerged as pivotal players in the immune processes associated with ASD, impacting neuroinflammation, autoimmunity and gastrointestinal health. They interact with other immune cells, release mediators that influence neurological processes, and help maintain the integrity of the blood-brain and gut barriers. Evidence of alterations in these processes in ASD patients, supported by extensive data from relevant animal models, has highlighted disruptions in these processes among individuals with ASD, underscoring the critical role of MCs in ASD pathology.

Current ASD treatments primarily aim at managing symptoms rather than addressing underlying mechanisms. However, targeting MC activity may represent a promising innovative approach for intervention. The development of novel MC inhibitors could significantly enhance our understanding of ASD pathobiology while potentially offering therapeutic benefits for a defined subset of individuals with ASD, improving their symptoms and quality of life.

 

Alzheimer’s research is very well funded and so we already have results from the use of Masitinib in humans.

 

Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial

Abstract

Background

Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer’s disease (AD).

Methods

Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12–25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population.

Results

Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, −1.46 (95% CI [−2.46, −0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [−0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of −2.15 (97.5% CI [−3.48, −0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [−0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [−0.48, 2.50]) (representing an overall functional improvement) versus −0.81 (95% CI [−2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib’s known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed.

Conclusions

Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data.

 

Not surprisingly there is a similar study in MS.

 

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Discussion

Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data.

 

Masitinib has already been patented to treat ALS the motor neuron disease.

 

Masitinib  for autism?

I think the people who respond to cromolyn sodium, but feel it lacks potency would be the ones who might benefit.

You either consult Prof Theoharides, or the local vet (It’s a doggy medication).

 

 

Low dose Efavirenz to activate CYP46A1 to reduce brain cholesterol 

Our reader Katya did raise the idea, a few months ago, of low dose Efavirenz to lower cholesterol in the brain.

Elevated cholesterol in the brain is a feature of some specific variants of autism.

Elevated brain cholesterol is a contributing factor in many cases of Alzheimer's, but it is not a universal feature. It depends which version of the APOE gene the person carries.

The brain has a lot of cholesterol in it and all of it was produced there.

The brain cannot rely on peripheral cholesterol transport due to the blood-brain barrier. The enzyme CYP46A1 ensures local cholesterol balance in the brain, by facilitating clearance of excess cholesterol to maintain healthy neuronal and synaptic functions.

Proper cholesterol metabolism, facilitated by CYP46A1, supports synaptic remodeling, plasticity, and repair, which are critical for cognitive function.

Dysregulated cholesterol levels in the brain can impair synapse function, and CYP46A1 helps prevent these disruptions.

Efavirenz is a drug used in the treatment of HIV. Interestingly, at subtherapeutic doses, it has been shown to activate CYP46A1 and so increase cholesterol clearance from the brain.

 

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease

Background

Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. 

Methods

This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.

Results

In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects.

Conclusions

Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology.

 

It looks like 50mg a day of efavirenz is an effective option to reduce levels of cholesterol in the brain. Interestingly it is not effective in people already taking a high dose of atorvastatin. This should not be a surprise since atorvastatin will have already lowered cholesterol in the brain.

So to lower cholesterol in the brain you could use the 50mg of efavirenz, or if that was not possible then 40mg of atorvastatin  would be an option. The trial showed using both drugs together was pointless.

  

First patient completes new trial to test Alzheimer’s medication

13 March 2025

The existing HIV medication Efavirenz may potentially also be effective for Alzheimer’s patients, Vrije Universiteit Amsterdam neuroscientist Rik van der Kant and Amsterdam UMC neurologist Jort Vijverberg discovered. This fall, a clinical trial has begun at Amsterdam UMC, and the first patient has just completed the trial.

Participants are still being recruited. The research is led by Rik van der Kant and Jort Vijverberg (Amsterdam UMC - Alzheimer Center Amsterdam). Van der Kant has been researching new drugs for Alzheimer’s disease for years, using groundbreaking technology that allows him to test hundreds of potential medications simultaneously. 

Promising step  
“I discovered that cholesterol buildup in brain cells of Alzheimer’s patients directly leads to an accumulation of the toxic proteins Tau and Amyloid,” Van der Kant explains. “Efavirenz turned out to be suitable for reversing this buildup. It's very special and unique to be able to do all of this ourselves, within the walls of Amsterdam UMC." Vijverberg is also hopeful. “We are very curious to see how this medication will work in Alzheimer's patients. Of course, we still have to see the results, but I consider it a promising step in the right direction.” 

 

The Alzheimer’s APOE story

Apolipoprotein E (APOE) plays a critical role in lipid transport and cholesterol homeostasis in the brain. It facilitates the redistribution of cholesterol and other lipids between cells for membrane repair, synaptogenesis, and other neuronal functions.

In the brain, APOE interacts with specific receptors, such as the low-density lipoprotein receptor (LDLR), to regulate cholesterol and amyloid-beta (Aβ) clearance.

APOE Variants:

There are three major alleles of the APOE gene: ε2, ε3, and ε4, which encode the respective protein isoforms.

APOE ε2: Rare and protective against AD.

APOE ε3: The most common variant with neutral risk for AD.

APOE ε4: A strong genetic risk factor for AD.

 

APOE ε4's Impact on Cholesterol and Aβ

Reduced Cholesterol Transport: APOE ε4 is less efficient in binding and redistributing cholesterol compared to APOE ε3 or ε2. This inefficiency can lead to local cholesterol dysregulation in the brain, particularly in neurons and astrocytes.

APOE ε4 is less effective in promoting Aβ clearance via receptor-mediated pathways (e.g., LDLR, LRP1).

The isoform is associated with an increased tendency of Aβ peptides to aggregate, contributing to plaque formation. 

Cholesterol Accumulation and AD Pathogenesis:

Elevated cholesterol levels in neuronal membranes can favour the activity of β- and γ-secretases, enzymes involved in Aβ production.

The inefficient lipid transport by APOE ε4 exacerbates cholesterol accumulation in affected brain regions, creating a feedback loop that promotes amyloidogenic processing.

 

 

Vitamin D in Alzheimer’s and Maternal Immune Activation Autism

Vitamin D’s role in Alzheimer’s disease has been widely studied, with growing evidence suggesting it may influence risk and progression, but it is not a cure or primary treatment.

Vitamin D appears to have a supportive role in brain health, potentially lowering the risk or slowing progression of Alzheimer’s disease by reducing inflammation, aiding amyloid clearance, and protecting neurons. However, vitamin D alone is not a standalone treatment for AD. Ensuring adequate vitamin D status is a simple, low-risk strategy that could contribute positively as part of a broader approach to brain health and dementia prevention.

In Japan researchers have recently found that they can prevent autism caused by maternal immune activation simply by giving a vitamin D supplement during pregnancy. This was in a mouse model, but what about its use as yet another method to prevent/reduce some human autism?

 

Supplementing with Vitamin D during Pregnancy Reduces Inflammation and Prevents Autism-Related Behaviors in Offspring Caused by Maternal Immune Activation 

Autism spectrum disorder (ASD), a neurodevelopmental disorder of unknown etiology with limited treatment options, has emerged as a significant public health concern. Studies have demonstrated that prenatal vitamin D deficiency is a risk factor for ASD development in offspring; however, the underlying mechanism remains unclear. In this project, vitamin D was administered orally to pregnant mice with/without the subsequent administration of polyriboinosinic polyribocytidylic acid (Poly(I:C)), which induced the maternal immune activation (MIA). Our results showed that vitamin D supplementation during pregnancy alleviated MIA-induced ASD-like behaviors in offspring. Moreover, vitamin D supplementation reduced the MIA-induced elevation of interleukin-6 (IL-6) and IL-17a levels in both the maternal ileum and fetal brains. It also suppressed signal transducer and activator of transcription 3 (Stat3) activation and the elevated expression of serum amyloid A1 and A2 (SAA1/2) in the ileum of MIA-affected pregnant mice. This study revealed that vitamin D may reduce the expression of IL-17a by inhibiting the IL-6/Stat3/SAA signaling pathway, thereby improving ASD-like behavior in offspring mice, and provide a new theoretical support for the prevention and treatment of ASD by scientific dietary interventions and nutritional supplement during pregnancy.

 

 

 

Menthol for Alzheimer’s and some Autism? 

I recall one reader, I think is was Natasa in London, mentioned that menthol should be a helpful autism therapy for some people. I see today that Nestle even holds an old patent on its use for autism.

The surprise is that just inhaling the smell of menthol has an anti-inflammatory effect in the mouse model of Alzheimer’s. 

 

Surprise Link Between Menthol And Alzheimer's Found in Mice

In recent years, scientists discovered something strange: When mice with Alzheimer's disease inhale menthol, their cognitive abilities improve.

It seems the chemical compound can stop some of the damage done to the brain that's usually associated with the disease.

In particular, researchers noticed a reduction in the interleukin-1-beta (IL-1β) protein, which helps to regulate the body's inflammatory response – a response that can offer natural protection but one that leads to harm when it's not controlled properly.

The team behind the study, published in April 2023, says it shows the potential for particular smells to be used as therapies for Alzheimer's. If we can figure out which odors cause which brain and immune system responses, we can harness them to improve health.

"The results suggest that odors and immune modulators may play an important role in the prevention and treatment of Alzheimer's and other diseases related to the central nervous system." 

 

Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells

 

 

 

 

Patent - Treatment or prevention of autism disorders using menthol, linalool and/or icilin

Current Assignee: Societe des Produits Nestle SA

 

Compositions for treatment or prevention of autism disorders are provided, and the compositions contain a therapeutically effective amount of a compound selected from the group consisting of Menthol, Linalool, Icilin and combinations thereof. Methods for treatment or prevention of autism disorders are also provided, and the methods include administering such compositions.

 

Menthol has shown promising effects in modulating inflammatory pathways, including those involving IL-1β and the NLRP3 inflammasome.

Menthol and IL-1β

• Menthol inhibits the production and release of pro-inflammatory cytokines, including IL-1β, which is a key mediator in various inflammatory conditions.
• Menthol primarily acts through transient receptor potential melastatin 8 (TRPM8) channels. Activation of TRPM8 can indirectly reduce inflammation by modulating neural and immune pathways.

Menthol and the NLRP3 Inflammasome

• Studies indicate that menthol may inhibit the activation of the NLRP3 inflammasome, a multiprotein complex responsible for IL-1β maturation and release.
• Menthol's ability to suppress oxidative stress and calcium influx, both of which are critical for NLRP3 activation, contributes to its anti-inflammatory effects.
• These properties make menthol a potential therapeutic candidate for diseases where the NLRP3 inflammasome plays a role, such as neurodegenerative diseases, autoimmune conditions, and metabolic disorders.

 

Conclusion

It looks like keeping an eye on research across a broad range of neurological conditions is a wise idea, if you want to treat autism.