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.

Agmatine, again shown beneficial in some autism

 

Albrecht Kossel discovered Agmatine in 1910. That year he won the Nobel prize for medicine. The Albrecht Kossel Institute for Neuroregeneration, in Rostock Germany, is named after him.

 

For those people who keep an eye on the autism research, a recuring observation will have been how the same therapies keep on coming up, sometimes with a new twist. A good example that came up recently is Agmatine, a cheap supplement.

Agmatine is a naturally occurring compound in the body derived from the amino acid arginine, functioning as a neuromodulator and cellular regulator with benefits spanning neurological, cardiovascular, metabolic, and anti-inflammatory systems.

Monty, now aged 21 with autism, has been taking 750mg of Agmatine daily for eight years. In his case it reverses both mental and physical lethargy, like fitting a new set of alkaline batteries to an old toy.

Agmatine has many biological effects, the one that works in our case is its effect on nitric oxide (NO). Agmatine increase eNOS which improves vascular health, reduces blood pressure, enhances circulation. Agmatine can boost mitochondrial function, which also improves energy production and physical endurance.

Agmatine has many other effects, including:

1. Neurological Effects

Neuroprotection. Agmatine reduces oxidative stress and excitotoxicity by modulating glutamate and nitric oxide pathways.

Mood Enhancement. Agmatine acts as an antidepressant by interacting with serotonin and adrenergic receptors.

Cognitive Support. Agmatine may enhance memory and learning by promoting synaptic plasticity.

Pain Modulation. Agmatine offers analgesic effects by influencing opioid receptors and pain-related neurotransmission.

Seizure Protection. Agmatine demonstrates anticonvulsant properties in some animal studies.

 

2. Metabolic and Hormonal Effects

Insulin Sensitivity. Agmatine improves glucose uptake and reduces insulin resistance, aiding in blood sugar regulation.

Fat Metabolism. Agmatine may support weight management by modulating appetite and energy expenditure.

Stress Response: Agmatine regulates the hypothalamic-pituitary-adrenal (HPA) axis, improving the body’s response to stress.

 

3. Cardiovascular Effects

Blood Pressure Regulation. Agmatine enhances endothelial nitric oxide synthase (eNOS) activity, promoting vasodilation and lowering blood pressure.

Heart Protection. Agmatine may reduce the risk of atherosclerosis by improving endothelial function.

 

4. Anti-Inflammatory Effects

Cytokine Modulation. Agmatine reduces pro-inflammatory cytokines and markers like TNF-α and IL-6.

Oxidative Stress Reduction. Agmatine acts as an antioxidant, reducing damage from reactive oxygen species (ROS).

 

5. Musculoskeletal Effects

Bone Health: Agmatine supports bone remodeling by regulating osteoblast and osteoclast activity.

Muscle Recovery: Improves recovery after exercise by reducing inflammation and oxidative stress.

 

6. Gastrointestinal Effects

Gut Barrier Protection. Agmatine may enhance gut lining integrity and reduce inflammation.

Microbiota Interaction. Agmatine can indirectly influence gut microbiota through anti-inflammatory pathways.

 

7. Immune System Effects

Immunomodulation. Agmatine balances immune responses by reducing excessive inflammation.

Autoimmune Benefits. Agmatine shows potential in alleviating symptoms of autoimmune diseases by modulating iNOS activity.

 

Agmatine has been shown effective in various models of autism, including valproic acid-induced and Fragile X.

Agmatine signalling has been recently been shown to have a bidirectional interaction with the gut microbiome and its neuroprotective and anti-ageing functions have been suggested to depend on the resident microbes in that person’s gut. So it will not work for all.

Agmatine has even shown to have a benefit when given prenatally, to prevent autism.

The recent paper that I stumbled upon is this one below. There are two well-studied chemicals produced in the gut can induce autism, or just make existing autism worse. One is P-cresol and the other is propionic acid. Our reader Stephen is interested in ways to low P-cresol. A recent finding was that nutmeg lowers P-cresol and can indeed modulate colon cancer – no surprise to those who follow Chinese traditional medicine. Reducing propionic acid is the basis for the popular Nemechek Protocol for autism, which involves increasing fiber (inulin) in the gut, to favour butyric acid production over propionic acid. Butyric acid has many positive effects.

In the new paper the researchers looked at how propionic acid causes autism symptoms and they identified reduced agmatine as the problem.

Supplementing agmatine reversed the behavioral and biochemical alterations. Great!

We have already seen that the propionic acid induced model of autism can be reversed by NAC. Later in this post you will see that quercetin is also effective.

 

Postnatal propionic acid exposure disrupts hippocampal agmatine homeostasis leading to social deficits and cognitive impairment in autism spectrum disorder-like phenotype in rats

·        PPA reduced sociability and social preference and impaired learning and memory.

·        PPA treatment decreased agmatine and increase agmatinase in hippocampus.

·        PPA altered the glutamate, GABA, TNF-α, IL-6, BDNF levels and GFAP expression.

·        Agmatine reversed the behavioral and biochemical alterations induced by PPA.

·        Study suggests the role for hippocampal agmatinergic pathway in the etiopathogenesis of ASD.

 

I did then look up the research that has been published since I first investigated Agmatine as a potential autism therapy in humans and indeed started using it. There is a lot of research now existing.

 

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism

 ·        Single treatment of agmatine rescues social impairment in the VPA-induced animal model of autism.

·        Effect of agmatine in social improvement in the VPA model is induced from agmatine itself, not its metabolite.

·        Agmatine rescues repetitive and hyperactive behavior, and seizure susceptibility in the VPA model.

·        Overly activated ERK1/2 in the brain of the VPA model is relieved by agmatine.

 

Autistic-like behaviors are attenuated by agmatine consumption during pregnancy: Assessment of oxidative stress profile and histopathological changes in the prefrontal cortex and CA1 region of the hippocampus

Conclusion:

Overall, this investigation suggests that agmatine may be a potential candidate for the early treatment and even prevention of appearance of autism symptoms.

  

Agmatine relieves behavioral impairments in Fragile X mice model 

·        Fragile X syndrome showed an exaggerated NMDA receptor signaling, problems in synaptic transmission, and abnormal behaviors.

·        Agmatine is an endogenous polyamine and functions as a synaptic neurotransmitter.

·        Agmatine reversed these problems in the model of fragile X syndrome mice.

 

 

The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway

Results

The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. 

Conclusion

Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

  

The Prenatal Use of Agmatine Attenuates Social Behavior Deficits in VPA-Exposed Mice by Improving Neuron Loss

Results: Prenatal use of agmatine alleviated the anxiety behaviors of autistic mice in the marble burying test, open field test and three-chamber social interaction test. Prenatal use of agmatine blocked hippocampal neuronal damage and protected the maturity of neurons in autistic mice. 

Conclusions: The prenatal use of agmatine efficiently attenuated social interaction, learning and memory impairments in VPA-exposed mice by improving neuron loss. Agmatine is useful to block the occurrence of autism in offspring for the VPA-exposed pregnant women to an extent.

 

Neuroprotection by agmatine: Possible involvement of the gut microbiome?

·        Dysfunction of agmatinergic signalling is implicated in neuropathologies.

·        Agmatine is a multimodal neuroprotectant and a potential anti-ageing therapeutic.

·        Agmatinergic signalling elicits a bidirectional interaction with the gut microbiome.

·        Its neuroprotective and anti-ageing functions possibly depend on the resident microbes.

  

Effects of agmatine on radial-arm maze memory performance and autistic-like behaviors in a male rat model of autism

Conclusion

·        In a rat model of autism, spatial learning, and memory did not change. Agmatine rescued social and anxiety-like behavior in autistic animals.

 

Conclusion

I wrote extensively about Agmatine in my blog

https://www.epiphanyasd.com/search/label/Agmatine 

and in my book.

I have used 750mg a day for the last eight years. For me, no further research is needed!

Agmatine is sold as a cheap fitness supplement and is available in many countries, but not all.

You do wonder why more children with autism have not trialed it.

 

A few other interesting papers appeared recently, repeating what has been covered earlier in this blog. 

Oxytocin Improves Autistic Behaviors by Positively Shifting GABA Reversal Potential via NKCC1 in Early-Postnatal-Stage  

Overall, the results demonstrate that the early postnatal stage may be the unique critical period for oxytocin signaling to regulate GABA reversal potential and promote brain development for prosocial behaviors. These findings suggest an earlier intervention window and strategy for the clinical oxytocin treatment of autism.

 

This fits with idea of giving all new-born babies, delivered by C-section, a dose of oxytocin just after birth. These babies missed out on the mother’s surge in oxytocin during birth. The lack of oxytocin means that the GABA developmental switch may never takes place and neurons cannot mature. The result is autism and intellectual disability.

The body does have fall-back mechanisms that can trigger this switch, so not every baby delivered by C-section is autistic. But, humans have evolved to expect a dose of oxytocin at birth – let them have it.

I do like quercetin and it also popped up recently, again in respect to propionic acid induced autism.

 

Antioxidant-Effective Quercetin Through Modulation of Brain Interleukin-13 Mitigates Autistic-Like Behaviors in the Propionic Acid-Induced Autism Model in Rats

These findings, when interpreted together, suggest that quercetin exerts its neuroprotective effects by targeting oxidative stress and neuroinflammation, thereby preventing neuronal cell loss and alleviating behavioral deficits associated with autism spectrum disorders.

 

The final paper is about vagus nerve stimulation (VNS), which has also been extensively covered in this blog. VNS holds promise as a potential adjunctive therapy for autism, especially for symptoms related to autonomic dysregulation, anxiety, and epilepsy. The technology is getting fine-tuned.

 

Vagus Nerve Stimulation Erases PTSD

Prior research shows many PTSD patients fail to respond to standard treatments, making this approach especially promising. Future trials will explore the therapy further, aiming to offer new hope for those resistant to conventional methods.

Key Facts:

·         100% Remission: All participants were free from PTSD diagnosis six months after therapy paired with VNS.

·         Neuroplasticity Boost: VNS enhances brain rewiring, improving outcomes for therapy-resistant PTSD patients.

·         Next Steps: A double-blind Phase 2 trial is underway to confirm findings and move toward FDA approval.

 

Presume competence? Presume incompetence? Or just stretch boundaries?

I had a strange experience recently: for the very first time, a stranger asked me if my 21-year-old son has autism.

We were on holiday in Northern Spain, staying at a tiny hotel with just 6 rooms. The hotel was in a tiny village near San Sebastian that happened to be on the Camino del Norte, or Northern Way, which is a well known hiking route. The route was originally a pilgrimage to the city of Santiago de Compostella. The route seems to be popular with older Americans and British.

At breakfast there was one long table and so strangers were almost inevitably going to talk to each other. For Americans this is normal behaviour, but much less so for Europeans.

Monty was wearing a new replacement set of wireless headphones, which we had not quite figured out how to reliably connect to all his devices. As a result, he did look like the classic person with autism – wearing ear defenders and looking anxious.

“Excuse me, is he autistic?”, queried a guest who was walking the Camino del Norte with a friend.

It turned out that this fellow guest at the hotel had an adult son with autism, now in his 30s. His son is still doing ABA and does not get taken on holidays. “I'm impressed you take him with you,” he commented.

We felt it necessary to explain that Monty can do a lot: he completed mainstream school, passed his exams like the typical students, and now travels alone by public transport to “work” twice a week. He has been to China, Japan, South America and most of Europe. He can ski down black slopes, play the piano …

Our fellow guest told us how once his son had eloped and a police helicopter had been needed to find him, not surprisingly near an expanse of water. He did not attend school, due to his sensory issues.

This got me thinking about how we presume competence, or indeed incompetence.

These concepts have become quite a topic in the field of inclusive education. They have been rather stretched by the DEI people, but they are worth evaluating.

Most people assume that a person who behaves typically and is fully verbal must have full mental competence. We are surprised when that assumption proves false. For instance, Harvard University has introduced remedial math classes for some students; you wonder how that is possible. Similarly, some high school students in the U.S. cannot read analog clocks. Social media is awash with videos of young adults asking high school aged kids basic questions like "what is 33 divided by 3?" and having them unable to even make a reasonable guess. There is even a meme of teenage American girls being asked "in what country is Alaska?" and one answers Mississippi.

When we see a person who is not fully fluent verbally, most people tend to presume incompetence.

Last night, as Monty and I were completing our evening uphill “rucking” (fast walking with weights), I decided to check something. An out of breath Peter said “Mont, what is 33 divided by 3?” Without hesitation, he replied “eleven.” OK, I can use that example.   

   

Stretching boundaries

I did explain in Spain how we got to the point of travel independence. It was a step-by-step process and did not happen overnight, or by itself. I was asked how far away I was during this process. I did explain that with modern GPS tracking available on phones and air tags, it is now very much safer and easier. But things can and will go wrong – that is life. People learn by making mistakes – best make small ones, whilst you are still young!

I am a proponent of constantly stretching boundaries on the basis that taking many small steps forward can take you a long way. Just as it does for those older folk walking along the Camino del Norte.

Constantly stretching boundaries and gradually extending your comfort zone seems a good approach to autism. 

 

Mission Impossible in 4D

Monty’s big brother took me and Monty to see the new Mission Impossible film last week.  As we were about to buy the tickets, big brother said “Oh no, it's in 4D”. Watching movies in 4D is like being on a plane in severe turbulence. “No problem, he will enjoy it” was my response.

This was an example of presuming competence.

It was a great film to see in 4D, it really is a compelling experience. 100 times better than films in 3D.

Monty loved it.

 

What about those who are never competent?

For the DEI (i.e. not realistic) version of competence, here is a link to the TACA site.

 

Presuming Competence in Autism

Presuming competence means valuing all people, including those with autism, as whole individuals with the right to express their thoughts, feelings, and opinions. For individuals with autism, this includes the right to communicate, the right to be treated their age, to have their views and feelings respected, and to be involved in decisions about their lives, large or small. This article covers ways and things to consider when presuming competence in your loved one with autism. 

Speak Directly to the Person and in an Age-Appropriate Manner

Presume that everyone can understand what is being said.

Do not talk down to people with autism.

Do not use baby talk or a baby voice. 

Etc … 

The problem is that some people have impaired cognition, not just impaired verbal communications skills. They may never be able to safely cross a road independently, and some will grow up to be like a toddler in an adult’s body.

However, some young children diagnosed with level 3 autism have made such great strides in the early years that they have left their greatest challenges behind them. They should no longer be considered at level 3.

The Lancet Commission has wisely stated that you need to wait until the age of 8 before you can reliably diagnose profound autism. For these children, stretching boundaries seems a better and safer approach than presuming competence.

  

Excitatory/Inhibitory (E/I) imbalances as a unifying, treatable, feature of severe autism that cause Cognitive Impairment, Self-Injurious Behavior (SIB) and ultimately seizures in some

 

Autism is a complex condition that manifests in a range of symptoms, from social and communication challenges to sensory sensitivities and repetitive behaviors. Researchers long ago identified a key neurobiological mechanism that underlies many of the core and associated features of autism: excitatory/inhibitory (E/I) imbalances in the brain.

These imbalances, where the delicate interplay between neuronal excitation and inhibition is disrupted, offers a unifying framework to explain certain severe manifestations of autism, including cognitive impairment, self-injurious behavior (SIB), and seizures. Understanding E/I imbalance not only sheds light on the biology of autism but also opens new avenues for targeted therapies.

 

The Role of E/I Balance in the Brain

Neuronal circuits rely on a finely tuned balance between excitatory and inhibitory signals to function properly. Excitatory neurons promote the firing of signals, enabling processes like learning, memory, and sensory integration. Inhibitory neurons, on the other hand, dampen excessive activity, ensuring stability and preventing overstimulation.

In individuals with autism, this balance is often disrupted. Overactive excitatory signaling or insufficient inhibitory control can lead to hyperexcitability in certain brain regions, contributing to behavioral and neurological symptoms. This imbalance is influenced by a range of factors, including:

• Genetic mutations in key synaptic proteins (e.g., SHANK3, SCN1A, GABA receptor subunits).
• Neuroinflammation and oxidative stress.
• Developmental disruptions in synaptic pruning or circuit formation.

 

How E/I imbalances drives severe autism symptoms

 

Cognitive Impairment

E/I imbalance affects the prefrontal cortex and hippocampus, regions critical for cognitive functions like problem-solving, memory, and attention. Disrupted neural signaling in these areas impairs synaptic plasticity—the brain’s ability to adapt and learn—which can manifest as intellectual disability in some individuals with autism.

Studies have shown that restoring E/I balance in animal models can improve cognitive deficits, highlighting its central role in intellectual development.

 

Self-Injurious Behavior (SIB)

Self-injurious behaviors, such as head-banging or skin-picking, are often linked to dysregulated sensory processing and impaired impulse control. Hyperexcitability in brain regions like the amygdala can heighten stress responses, while altered pain thresholds caused by E/I imbalance may make some individuals less sensitive to injury.

Addressing the underlying imbalance can reduce the neural hyperactivity driving these behaviors and improve emotional regulation.

 

Seizures

Seizures are a common comorbidity in autism, affecting up to 30% of individuals. They arise directly from hyperexcitability in neural networks, where excessive excitation leads to abnormal, synchronized firing of neurons. Genetic conditions like Dravet syndrome, linked to mutations in sodium channel genes (e.g., SCN1A), exemplify the connection between E/I imbalance and epilepsy.

Therapies that stabilize E/I balance, such as GABA-enhancing drugs or ion channel modulators, have shown promise in reducing seizure frequency and severity.

 

Targeting E/I Imbalance: A Path Toward Better Treatments

Given its central role in severe autism symptoms, E/I imbalance represents a promising target for therapeutic intervention. Approaches to restore balance include:

 

Pharmacological Therapies

Bumetanide

Bumetanide is a diuretic that also affects neuronal chloride homeostasis by inhibiting the NKCC1 transporter. In autism, elevated intracellular chloride levels impair the function of GABA, shifting its action from inhibitory to excitatory. Bumetanide lowers intracellular chloride, restoring GABA’s inhibitory effect and reducing hyperexcitability. Clinical trials have shown improvements in social behaviors and reduced severity of core autism symptoms in some individuals.

 

L-Type Calcium Channel Blockers

L-type calcium channels play a role in synaptic plasticity and neuronal excitability. Excessive calcium influx can contribute to hyperexcitability and oxidative stress. Blockers like nimodipine and verapamil may help stabilize neuronal activity and have shown potential in reducing seizures and hyperactivity in preclinical studies.

 

T-Type Calcium Channel Blockers

T-type calcium channels are involved in regulating burst firing and thalamocortical oscillations. Dysregulation of these channels can contribute to sensory processing abnormalities and seizures. Agents like zonisade, traditionally used for absence seizures, may also offer benefits in addressing E/I imbalances in autism.

 

Memantine

Memantine is an NMDA receptor antagonist that modulates glutamatergic signaling. By dampening excessive excitatory activity, it can reduce hyperexcitability and improve cognitive and behavioral symptoms. Clinical studies have shown mixed results, with some individuals experiencing notable benefits in areas like communication and social interactions.

 

Low-Dose Clonazepam

Clonazepam, a benzodiazepine, enhances GABAergic inhibition by increasing the activity of GABA-A receptors. At low doses, it can stabilize neural circuits without causing significant sedation. It has been used off-label to manage anxiety, hyperactivity, and seizures in autism.

 

Valproate

Valproate is an anticonvulsant and mood stabilizer that enhances GABAergic signaling and reduces excessive excitation. It has shown efficacy in managing seizures and may also improve irritability and aggression in some individuals with autism.

 

Baclofen and R-Baclofen

Baclofen is a GABA-B receptor agonist that enhances inhibitory signaling. It can modulate overactive NMDA receptor activity, which may be beneficial in cases of excitatory dysfunction. Baclofen has been studied for its role in reducing repetitive behaviors and improving social interaction in preclinical models.

 

Taurine

Taurine is an amino acid with inhibitory properties that can enhance GABAergic activity and reduce excitatory signaling. It also acts as an antioxidant, mitigating oxidative stress linked to hyperexcitability.

 

Pioglitazone

Pioglitazone, a PPAR-gamma agonist, has anti-inflammatory effects that can indirectly stabilize neural circuits by reducing neuroinflammation associated with E/I imbalances. Preliminary studies suggest it may have benefits for behavioral symptoms in autism.

Other agents including

• Anti-inflammatory Drugs: Minocycline and mefenamic acid reduce neuroinflammation, which can exacerbate E/I imbalances.
• Ion Channel Modulators: Sodium channel blockers like lamotrigine and carbamazepine stabilize hyperexcitable neurons and may reduce both seizures and behavioral dysregulation.

 

Neuromodulation Techniques

• Transcranial Magnetic Stimulation (TMS): A non-invasive method to modulate cortical excitability.
• Transcranial Direct Current Stimulation (tDCS): Targets specific brain regions to enhance or suppress neural activity.

 

 

The Role of NMDA and GABA Receptors in E/I Imbalance

Excitatory NMDA receptors and inhibitory GABA receptors play central roles in maintaining E/I balance. NMDA receptor dysfunction, characterized by either hyperactivity or hypoactivity, is implicated in autism. Overactive NMDA receptors can amplify excitatory signaling, while underactive NMDA receptors can impair synaptic plasticity. Both scenarios disrupt neural communication and contribute to autism-related symptoms.

GABA receptors, particularly GABA-A and GABA-B subtypes, are essential for inhibitory control. Dysfunctional GABAergic signaling reduces the brain’s ability to counterbalance excitation, leading to hyperexcitability.

Baclofen’s modulation of GABA-B receptors exemplifies how targeting these systems can restore balance. By reducing NMDA receptor overactivation and enhancing GABAergic inhibition, baclofen addresses multiple aspects of E/I dysregulation.

 

NMDA receptor dysfunction

Addressing NMDA receptor dysfunction requires a nuanced approach because the receptor can be either hypoactive/underactive or hyperactive/overactive in autism, depending on the individual and the specific neural circuits involved. Treatments vary based on the direction of dysfunction:

 

Treating NMDA Hypofunction

In cases where NMDA receptors are underactive, excitatory signaling is insufficient, leading to impairments in synaptic plasticity, learning, and memory. Strategies to enhance NMDA receptor activity include:

1. D-Cycloserine
• Acts as a partial agonist at the glycine site of the NMDA receptor.
• Enhances receptor activity without overactivation, making it useful for improving social and cognitive functions in some individuals with autism.
2. Sarcosine
• A glycine transport inhibitor that increases synaptic glycine levels, promoting NMDA receptor activation.
• Preclinical studies suggest potential improvements in behavioral symptoms.
3. Glycine Supplements
• Directly increase the availability of a co-agonist required for NMDA receptor activation.
• May improve signaling in circuits where glycine levels are suboptimal.

 

Treating NMDA Hyperfunction

Excessive NMDA receptor activity can lead to excitotoxicity.  When there is too much glutamate or an overactive NMDA receptor, the influx of calcium ions into the neuron becomes excessive. This causes a series of harmful processes contributing to neuronal damage, increased oxidative stress, and seizures. Strategies to dampen NMDA receptor overactivity include:

1. Memantine
• An NMDA receptor antagonist that reduces overactivation without completely shutting down receptor function.
• Clinical trials in autism have reported mixed results but some individuals benefit in areas like hyperactivity and irritability.
2. Magnesium Supplements
• Magnesium acts as a natural blocker of the NMDA receptor under resting conditions.
• Supplementation can stabilize receptor activity and reduce hyperexcitability.
3. Low-Dose Ketamine
• At sub-anesthetic doses, ketamine modulates NMDA receptor activity and enhances synaptic plasticity.
• Emerging research suggests potential benefits for specific autism symptoms, although risks and side effects must be carefully managed.
4. Antioxidants (e.g., N-Acetylcysteine, Vitamin E)
• Reduce oxidative stress caused by NMDA receptor hyperactivity.
• Support neuronal health and may mitigate excitotoxicity.

 

Balancing NMDA Dysfunction

In some cases, the same individual may show hypoactivity in some circuits and hyperactivity in others.

Combining treatments tailored to the specific functional state of NMDA receptors in different brain regions. For example, Low-dose ketamine or memantine may help dampen excessive NMDA activity in the amygdala or basal ganglia, while D-cycloserine might be used to enhance NMDA function in areas like the prefrontal cortex.

  

Calcium, Sodium and Potassium Channels

Calcium signaling is critical for excitatory neurotransmission, as calcium ions mediate glutamate release and synaptic plasticity. Dysregulated calcium channels, such as overactive L-type or T-type channels, contribute to hyperexcitability and sensory abnormalities.

Sodium channelopathies, involving mutations in genes like SCN1A, directly impact neuronal firing rates. Excessive sodium influx leads to hyperactive neurons, causing seizures and other excitatory-driven symptoms. While calcium channels influence neurotransmitter release, sodium channel dysfunction primarily affects action potential generation.

Potassium channels, responsible for repolarizing neurons after firing, also play a key role in maintaining neural stability. Mutations in potassium channel genes can prolong neuronal firing and contribute to hyperexcitability.

 

Conclusion

While E/I imbalance is not the sole cause of autism, it is a key unifying feature that connects many severe symptoms. By targeting this imbalance, clinicians can develop more precise and effective treatments tailored to the individual’s needs. Early intervention, particularly during critical periods of brain development, holds the greatest potential for improving outcomes.

As we continue to unravel the complexities of autism, the concept of E/I imbalance serves as a key nexus to understand, and more importantly, treat the challenges faced by individuals with severe autism and their families. By restoring balance, to the extent possible, both in the brain and in daily life, we can empower those with severe autism to reach their full potential. 

People with mild autism are likely affected by less extreme E/I imbalances, but they may be more aware of them. They are likely easier to treat. The principles are the same. 

The issue of sound sensitivity can affect autism from level 0 (including self-diagnosed and ADHD) all the way to level 3; it is complex because it involves both an E/I imbalance and further issues. There will be a summary post on this subject.