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Showing posts with label Bumetanide. Show all posts
Showing posts with label Bumetanide. Show all posts

Wednesday 20 March 2024

Monty in Montevideo and Recent Advances in Autism Research



It is nice to have a city named after you and Monty finally visited “his” city, Montevideo in Uruguay.

I suppose my city would be St Petersburg, which I have visited several times.

A really impressive city in Latin America is Buenos Aires; it has a very large central area with beautiful architecture. It enjoyed several decades of great wealth, the “golden age,” when the city was laid out. In 1930 there was a military coup and the party was over. It has been boom and bust ever since.

We visited what they call the Southern Cone of Latin America, which is made up of Argentina, Chile and Uruguay. We went from Buenos Aires all the way down to Tierra del Fuego.

Santiago, the capital of Chile, looks to be booming. It has a small historic centre and everything else is new.

Montevideo was more what I expected, except for the graffiti everywhere which makes it look less safe than it likely is. Uruguay has many beautiful beaches, but until you get away from the vast River Plate estuary (Río de la Plata = river of silt) and to the Atlantic ocean the water is a dirty brown colour.  Monty would not go in the water.

Southern Chile and Argentina have some stunning scenery with volcanoes, mountains and glaciers.  It looks great, but it is no longer the cheap backpacker destination it once was.

 







 



Back to the Autism Research

The highlight from the recent research comes from The RIKEN institute in Japan. It does go some way to explaining why so many people with autism appear to have nothing in their genetic results to explain their condition.

Normally, when you have your state of the art whole genome screening (WGS) the geneticist who interprets the results is looking for mutations in one of the many hundreds of known “autism genes” and nowadays, hopefully, in the non-coding areas next to them. Whole exome screening (WES) just looks at the 2% of the genome that has the instructions for how to make each of your 22,000 genes. The other 98% includes things like promoters that increase activity of a specific gene.

Many people with autism appear to show no mutations that are relevant.

The Japanese have figured out one of the reasons why this is the case. There are other reasons.

Our genetic material is not stored on something like a long role of paper, which is like a two-dimensional object.  It is a three-dimensional twisted object all folded up. As a result, the DNA physically closest to each autism gene may not be the part expected. The Japanese use the term “topologically associating domain” (TAD) to define which zones of DNA are actually interacting with each other.

They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes.

This means that geneticists now need to go back to school and learn about the TAD of each autism gene. Or else just replace the geneticist with an AI generated report.

 

Mutation butterfly effect: Study reveals how single change triggers autism gene network

Researchers in the RIKEN Center for Brain Science (CBS) examined the genetics of autism spectrum disorder (ASD) by analyzing mutations in the genomes of individuals and their families. They discovered that a special kind of genetic mutation works differently from typical mutations in how it contributes to the condition. In essence, because of the three-dimensional structure of the genome, mutations are able to affect neighboring genes that are linked to ASD, thus explaining why ASD can occur even without direct mutations to ASD-related genes. This study appeared in the scientific journal Cell Genomics on January 26.

The researchers analyzed an extensive dataset of over 5,000 families, making this one of the world's largest genome-wide studies of ASD to date. They focused on TADs-;three-dimensional structures in the genome that allow interactions between different nearby genes and their regulatory elements. They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes. In this way, the new study explains why mutations can increase the risk of ASD even when they aren't located in protein-coding regions or in the promotors that directly control the expression of ASD-related genes.

 

"Our most important discovery was that de novo mutations in promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated through interactions in the three-dimensional structure of the genome."  

Atsushi Takata at RIKEN CBS

 

 

Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk

Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.

 

Bumetanide

 

I did come across a Chinese study with an eye-catching title:-

 

Can bumetanide be a miraculous medicine for autism spectrum disorder: Meta-analysis evidence from randomized controlled trials

 

Highlights

    • Bumetanide showed significant and large effects on the overall core symptoms of ASD.
    • Bumetanide’s efficacy on ASD is influenced by subjects’ age, dosage form, duration.
    • Results of RCTs on bumetanide in ASD are moderated by study designs, measurement tools

A systematic search was conducted on PubMed, EMBASE, MEDLINE, PsyclNFO, Web of Science, Clinical Trials.gov, and references in reviews from the earliest available date to September 2023. Randomized controlled trials (RCTs) were identified that evaluated the efficacy of bumetanide in improving overall core symptoms (OCS) of ASD. Therefore, nine studies with 1036 participants were included in the study.

Results

Bumetanide showed significant effects on OCS of ASD (WMD = 1.91, p = 0.006), particularly in sub-domains including relation to inanimate objects, adaption to environment changes, auditory response, near sensory responses, anxiety and hyperactivity. Moderating analysis indicated that a significant effect size of bumetanide on OCS of ASD was observed in specific subgroup, including 3–6 years old (WMD = 1.08, p = 0.008), the tablet (WMD = 2.80, p = 0.003), 3-month intervention (WMD = 2.54, p = 0.003), and the single-center studies (WMD = 2.80, p = 0.003).

Conclusions

Bumetanide has a large and significant impact on the OCS of ASD. Given the limited number and quality of included RCTs, future research should prioritize conducting large-scale trials focusing on sub-parameters or specific clinical features to comprehensively evaluate the efficacy of bumetanide in subpopulations of children with ASD.

Meanwhile, Professor Ben Ari has written another paper on why the phase 3 trial failed and has also published a book.

 

Bumetanide to treat autism spectrum disorders: are complex administrative regulations fit to treat heterogeneous disorders?

Introduction:

Extensive experimental observations suggest that the regulation of ion fluxes and, notably, chloride are impacted in autism spectrum disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1 cotransporter inhibitor Bumetanide has been shown to attenuate electrophysiological and behavioral features of ASD in experimental models. Both pilot and phase 2 double-blind randomized independent trials have validated these effects with thousands of children treated successfully. Both brain imaging and eye tracking observations also validate these observations. However, final large phase 3 trials failed, with no significant differences between placebo and treated children.

Methods:

Here, I discuss the possible reasons for these failures and discuss the exclusive reliance on complex patent cooperation Treaty (PCT) regulations. Indeed, available data suggest that bumetanide responders could be identified by relying notably on EEG measures, suggesting that biological sub-populations of patients might benefit from the treatment.

Results:

These observations raise important debates on whether treating only a % of children with ASD is acceptable.

Discussion:

It is likely that in many disorders, the heterogeneity of the pathological event precludes a single general treatment for all, suggesting that trials centered on selective populations of responders might be essential for large clinical trials to succeed.

  Here is the new book:-

Treating Autism with Bumetanide

https://www.cambridgescholars.com/product/978-1-5275-1890-2/

In spite of its high incidence, extensive media coverage and major clinical burden to families, there is not a single approved European or American drug treatment of Autism Spectrum Disorders (ASDs). The dominant genetic and psychiatric approaches to treat ASDs have various limitations, suggesting that a novel global approach to understand and treat ASDs is warranted. Based on the authors’ converged expertise on brain development, ASD treatment and brain imaging, this book provides a fresh view of the disorder which is validated by experimental imaging and large clinical trials, culminating in the first large phase 3 final pediatric trial (on 400 children in EU countries and the US) using a repositioning of a drug used for decades to treat hypertension and edema. The convergence of experimental and clinical data on this disorder is unprecedented, confirming the potential of the drug to be the first pediatric treatment of ASDs.

After explaining the mechanisms underlying ASDs, we describe specific cases of children who, after treatment, considerably improved their sociability and reduced their agitation. The book also discusses the skepticism that the authors met from the tenants of pure genetics and psychiatry, and why the abyssal poverty of information on developmental disorders has hampered progress in understanding and treating ASD.

 

Bumetanide dosage is key – “wonderful effects from increasing from 0.5mg to 1mg” 

One recuring feature I have noticed from bumetanide use in the United States is the low dosage often used, as if these doctors want to show the drug is ineffective.

A reader recently contacted me about his young son who responded to the low dose of 0.5mg, but his autism doctor would not increase the dose.  The parent took matters into his own hands and increased the dose and then wrote to tell me about the “wonderful effects.”

 

Diuresis has stopped, but restarts at a lower dose

In a minority of cases bumetanide causes no diuresis. The question is whether it can have any effect in the brain if it causes no diuresis. Has the drug been absorbed at all?

One reader contacted me to tell me that her son, who has responded well to bumetanide for several years, stopped experiencing any diuresis. Then she told me that when she reduces the dose the diuresis returns.

There are many possible explanations, but perhaps those people who find bumetanide causes no diuresis should try a lower dose and see what happens.

 

Vasopressin/Desmopressin

Much of the research into the hormone vasopressin comes from Stanford. They have published a string of papers over the years. I think they are definitely on to something, but they are taking their time and may never commercialize the result.  

The very recent one is:

Vasopressin deficiency: a hypothesized driver of both social impairment and fluid imbalance in autism spectrum disorder

 

For some reason there is no abstract. 

Thanks to our reader Seth, I have now added the link below that takes you directly to  Stanford's website, which holds the full text version of the paper. 

https://med.stanford.edu/content/dam/sm/parkerlab/documents/da035ad7-7c80-41bd-a9a6-ee03a8bcc58d.pdf


The same group previously published a paper showing that people with ASD have a reduced level of vasopressin in their spinal fluid. As you can see in the chart below the level of oxytocin was normal.

There have also been successful trials using intranasal vasopressin in humans.


Cerebrospinal fluid vasopressin and symptom severity in children with autism

 



Vasopressin and oxytocin are closely related hormones and possibly some interactions are not yet fully understood.

Both these hormones can be given via a nasal spray.

 

The Bumetanide-Vasopressin interaction

Under normal circumstances you would never combine vasopressin with a diuretic.

Vasopressin stops you peeing and that it is why it is given to some children who wet their bed at night.

Bumetanide is a fast-acting diuretic that causes you to pee a lot.

So if you gave a diuretic to an elderly overweight person to reduce their blood pressure, it would be mad to also prescribe vasopressin.  The drugs are therefore contraindicated.

In autism we do not actually want the diuretic effects of bumetanide. We just want its effects on the brain.

The social and emotional beneficial effects of vasopressin have already been established by the existing Stanford research.

The combined effects of bumetanide + intranasal vasopressin might then be a win-win. Less autism and without the diuresis.

I was contacted long ago by a father whose daughter was prescribed Desmopressin, a synthetic analog of vasopressin that is an approved drug, and her autism markedly improved.

The Stanford research in humans uses a nasal spray that they have compounded specially rather than the commercially available Desmopressin.

 

 



Thursday 22 June 2023

Autism Research Merry-go-round Keeps Turning

 


Today’s post again shows that many issues raised in previous posts keep on coming back  is that good news? Only you can decide.

I start with the “old chestnut” (English idiom to imply “a tired old story”) of the Autism Tsunami. 

Then we see what has come up in the world of autism interventions in the research in the last 3 weeks, most of which regular readers will already be aware of.

·        Autism Tsunami – real or not?

·        Vitamin D

·        Bumetanide

·        Ibudilast

·        Niclosamide

·         Non-invasive brain stimulation

·         Simvastatin 

I noted the research about autism incidence coming from Northern Ireland because it was published in the Belfast News Letter.  These days it has a tiny subscription, but I am one of those who know it is the world's oldest English-language general daily newspaper still in publication, having first been printed in 1737. In 1972 a bomb warning was called in to the paper's office and, as people evacuated, an explosion went off nearby killing several people and injuring many more. Back in the early 1990s, when some people in Northern Ireland were still blowing up others with bombs, I made a visit to Northern Ireland to meet the management of this newspaper. 

Their recent article on autism incidence is very well researched considering how only about 8,000 copies are published. Keep up the good work!

Idea that 5% of all Northern Ireland's children are autistic is 'a fantasy' claims international expert

Professor Laurent Mottron was speaking to the News Letter following a claim that the rate of autism in Northern Ireland is double the rate in the rest of the UK.

Back in 2019 Prof Mottron had authored a report warning about a tsunami of over-diagnosis, saying that soon "the definition of autism may get too vague to be meaningful, trivializing the condition"

“If this trend holds, the objective difference between people with autism and the general population will disappear in less than 10 years," he had said then – and has now indicated that this “fuzziness” is what’s helping swell the numbers in Northern Ireland.

Meanwhile Jill Escher, the president of the National Council on Severe Autism, takes a different view.

She says that evidence indicates the "skyrocketing" rate of autism in Northern Ireland is real, adding: "It boggles my mind that it is not the subject of the highest possible alarm and inquiry."

"One in 20 children in Northern Ireland of school age has a diagnosis of autism," he told MPs.

"[It is] one in 57 in the rest of the UK. The need in Northern Ireland is significantly different."

To put that in perspective, that would mean 5% of Northern Irish children are diagnosed with autism, compared with 1.8% in the rest of the UK.

Prof Mottron, a psychiatrist based at Montreal University, told the News Letter "numbers such as 5% are pure fantasy... these numbers correspond to the part of the general population which has less overt socialisation, which has minimally to do with prototypical autism". 

There is a "current fuzziness of autism diagnosis and over-inclusivity," he said, leading to "a situation of perfect confusion between autistic traits and prototypical autism" (that is, mixing up people who exhibit some tendencies of autistic people with people who actually have the full-blown condition). 

"The scientific 'quasi consensus' would be around 1% everywhere on the planet,” he added.

 

So on one side we have Jill Escher and her NCSA and on the other we have a French/Canadian researcher.  This time Laurent Mottron but in my blog posts I quoted Éric Fombonne.

A paper that was mentioned both in my blog and critiqued by Jill about autism incidence and cost just got retracted.  In reality a better word is “cancelled.”  The 3 authors are very much in the politically incorrect camp of the autism debate.

I was surprised it ever got published.  

Controversial ‘cost of autism’ paper retracted 

Citing methodological issues and undeclared conflicts of interest, an autism journal has retracted a paper that forecast the prevalence and cost of autism.

The retraction note, posted last week, comes two years after Spectrum reported on backlash surrounding the paper, which was published in the Journal of Autism and Developmental Disorders in July 2021. A month after publication, the journal added an editor’s note that the study was under investigation because of criticisms of its conclusions. 

“I am glad to see that it was retracted, although at a pace that maybe is a bit frustrating in terms of how long it took. But it was the right choice,” says Brittany Hand, associate professor of health and rehabilitation sciences at Ohio State University in Columbus.

Outside experts who reviewed the paper on the journal’s behalf found that it misrepresented the rise in autism diagnoses and gave “insufficient attention” to some potential causes of the increase, such as improved surveillance and changes to the diagnostic criteria. The authors also used “higher estimates and assumptions that inflated costs,” according to the retraction note.

The authors — Mark Blaxill, Toby Rogers and Cynthia Nevison — all disagree with the journal’s decision, the note also says.

The cancelled paper is here:-

Autism Tsunami: the Impact of Rising Prevalence on the Societal Cost of Autism in the United States

 

I assume Blaxill was the driving force behind all the math, because he is the ex- management consultant, with a son with severe autism that his dad attributes to vaccines.

What I found bizarre in their paper was that they has a prevention scenario, based on what they think has already happened in rich parts of California, where they think autism incidence is falling.  It is not falling, all that is happening is that wealthy Californians are paying for treatment using insurance or their own money, and no longer burdening the State.

The “rainbow” researchers that wanted the paper retracted think that preventing autism is akin to eugenics and Dr Mengele. According to Peter, treating autism is good, while Dr Josef Mengele, byname Todesengel (German: “Angel of Death”) was as bad as you can get.    

Jill Escher and her NCSA think that you cannot prevent autism.  According to Peter, you can both minimize the incidence and severity of autism. 

A bugbear of our reader Tanya is that the NCSA have a pet hate of facilitated communication and in particular the rapid prompting method (RPM). This method worked for Tanya’s son and it opened the door to independent, un-facilitated communication. 

Always keep an open mind.

 

 

 

“our Prevention scenario is based on real rates observed among wealthy white and Asian children in the California DDS.  Severe ASD prevalence has flattened and even declined among these children since birth year 2000, suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD. The Prevention scenario assumes that these parental strategies and opportunities already used by wealthy parents to lower their children’s risk of ASD can be identified and made available rapidly to lower income children and ethnic minorities, who are currently experiencing the most rapid growth in ASD prevalence”

 

New Paper Makes Case that Autism Tsunami May Threaten American Economy

A major weakness in the analysis was the “Prevention Scenario” in which future costs were projected based on “what might be possible if strategies for reducing ASD risk are identified and addressed in the near future.” As I think everyone knows, at this time there is no way to prevent autism. But the authors use the observation that autism in the DDS is declining among wealthier white families, and thus “suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD.” No, it’s far more likely that wealthier families are not entering their children into the system because they access services through insurance and school districts instead.

 

Vitamin D as a cause of autism has been discussed for decades.  As the title below puts it – a never-ending story. Our reader Seth Bittker even wrote a paper about it. He later wrote a paper about the use Acetaminophen/Paracetamol in children under two as a risk factor in developing autism. Good work Seth!

 

Maternal Vitamin D deficiency and brain functions: a never-ending story 

A large number of observational studies highlighted the prevalence rates of vitamin D insufficiency and deficiency in many populations as pregnant women. Vitamin D is well known to have a crucial role in differentiation and proliferation, as well as neurotrophic and neuroprotective actions in brain. Then, this micronutrient can modulate the neurotransmission and synaptic plasticity. Recent results from animal and epidemiological studies indicated that maternal vitamin D deficiency is associated with a wide range of neurobiological disease including autism, schizophrenia, depression, multiple sclerosis or developmental defect. The aim of this review is to provide a state of the art on the effect of maternal vitamin D deficiency on brain functions and development.

4.2.2. Autism

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with repetitive behaviour and difficulties in social interaction, communication and learning. Several murine studies and cohorts have demonstrated that early exposure to low levels of VD during pregnancy could be a risk factor for ASD. In 2019, Ali et al. aimed to find out the impact of a maternal VDD on early postnatal, adolescent and adult offspring. By assessing righting reflex and negative geotaxis, they found out that the pups from deficient dams showed a delay in their motor development. P12 rats from deficient females also exhibited increased ultrasound vocalization indicating an alteration in their vocal communication. Adolescent and young adult rats displayed an altered stereotyped repetitive behaviour as they had a reduced digging behaviour. Adolescent rats had less social interaction with longer latency to interact, which was not found in adult rats; however, adults were more hyperactive but showed no anxiety like behaviour.  In another animal study, maternal VDD induced an increase in the vocalizations of the pups accompanied with a decrease in cortical FoxP2, decrease in social behaviour and impaired learning and memory were observed in adult males (Table 1). Using data from the Stockholm youth cohort, Magnusson et al. examined a population of 4-17-year-old children exposed to low levels of VD during gestation and was able to report a positive association between maternal VDD and ASD. Analysing the same cohort, Lee et al. suggested that high levels of VD during pregnancy were associated with a moderate decrease in risk of ASD in the offspring. A prospective study of a multi-ethnic cohort in the Netherlands (generation R study) has also shown an association between maternal mid-gestation VDD and a two-fold increase in the risk of autism in children (Table 2). Interestingly, VD supplementation seems to clinically improve ASD symptoms of affected children.

 

People do associate this blog with Bumetanide.  Yet another paper has been published showing the benefits of this therapy for autism.

 

EEG-based brain connectivity analysis in autism spectrum disorder: Unravelling the effects of bumetanide treatment 


Highlights

 

·        We investigated the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment.

·        We found statistically significant differences between pre and post intervention in the connectivity patterns using repeated measures analysis of variance (ANOVA).

·        We found that the number of strong connections in response to sad image stimuli seem to be less compared with that of the other two stimuli, especially in the central area.

·        We found that the changes in brain connectivity between pre and post intervention is more significant in response to sad image stimuli.

 

Emerging evidence suggests that cognitive impairment associated with brain network disorders in people with autism could be improved with medications such as bumetanide. However, the extent to which bumetanide is effective in improving brain function in these individuals has not been adequately studied. The main purpose of this study is to investigate the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment. We used electroencephalography (EEG) data of nine participants recorded during the face emotion recognition activity in two stages before and after bumetanide treatment. Brain connectivity matrix was calculated using a neural network-based estimator. Graph criteria and statistical tests have been used to determine the effects of bumetanide treatment on children and adolescents with autism. Bumetanide treatment significantly alters the brain connectivity networks based on stimuli type. Differences in brain connectivity related to the sad stimuli are more significant. The most of the significant changes of the strength graph metric was in the occipital electrodes and electrodes related to the right hemisphere. These results suggest that bumetanide may affect effective connectivity and be used a promising treatment for improving social interactions in patients with autism. It also suggests that brain connectivity patterns can be considered as a neural marker to be used in the development of new therapies. 

I have also covered in sometimes painful details the potential to treat autism and increase cognitive function using PDE (Phosphodiesterase) inhibitors. One of our psychiatrist readers is a huge fan of Pentoxifylline and takes it himself.

I was recently asked how to obtain Ibudilast.  It is approved in Japan as an asthma drug. Sometimes it is called Ketas and you can get it from an “International Pharmacy” in Germany/Switzerland if you have a prescription. 

I also wrote about repurposing Roflumilast, which as Daxas is approved all over the world as a therapy for severe asthma (COPD). This drug at a 1/5th dose has been patented as a cognitive enhancer.

 

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder

 

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats.

Methods

Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum.


Key findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage.

Conclusions

Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

 

 

I have also written widely about repurposing certain anti-parasite medicines to treat autism. This is not because I think parasites cause autism, it is the secondary modes of action.

 

 

Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis

 

 

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer’s Disease and Parkinson’s Disease, as well as various cancers by targeting ERK/MAPK, it’s efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

 

Note that in earlier posts I explored RASopathies as potentially treatable types of intellectual disability (ID). We also have RAS-dependent cancers as a discrete treatable sub-type of cancer.


The ERK/MAPK pathway is known to interact with multiple genes that have been implicated in autism, and genome-wide association analysis of the same have supported these findings. As such, a dysregulation of this pathway has been found to result in many CNS disorders, including ASD-related syndromes, in many studies. These syndromes are collectively known as Rasopathies, due to the fact that the affected genes include those encoding for elements which function together with Ras, a G-protein responsible for activating ERKs (Levitt and Campbell 2009; Tidyman and Rauen 2009). It has been found that ASD is linked to the occurrence of many Rasopathies, and there have been multiple reports suggesting the possible relation of ERK/MAPK pathway defects with the incidence of ASD (Vithayathil et al. 2018; Aluko et al. 2021)⁠⁠. Moreover, a detailed study has found that single nucleotide polymorphisms (SNPs) in the ERK/MAPK-related genes are more common in subjects presenting with idiopathic ASD.

 

Niclosamide is an FDA-approved antihelminthic drug which is routinely used to treat tapeworm infections by inhibiting their mitochondrial oxidative phosphorylation and ATP production. In addition, it has long been known to have significant immunomodulating activity, and has been shown to inhibit a number of signaling pathways, including the Wingless-related integration site (Wnt)/β-catenin, nuclear factor kappa B (Nf-κB), signal transducer and activator of transcription 3 (STAT3), and mammalian target of rapamycin (mTOR) (Chen et al. 2018). However, while these targets are known to be rather well-characterized in terms of the effect that niclosamide has on them, there are also other targets, including the phosphoinositode 3 kinase/Akt (PI3K/Akt) and ERK/MAPK pathways, that are seen to be downregulated by the agent. Hence, given the possible relation of the ERK pathway in autism, there has been interest in the potential role of niclosamide in the management of the prognosis of ASD. This article aims to discuss the possible therapeutic benefit of niclosamide in the treatment of autism spectrum disorders.

 

Now I know that parents like the idea of treating autism with various gadgets you can strap on to your head  things like Transcranial Magnetic Stimulation (TMS). I must say I liked my old post on Photobiomodulation/cold laser/low level laser therapy.


Epiphany: Low Level Laser Therapy (LLLT) for Autism – seems to work in Havana


From China we have a new round-up paper, but the full text does not yet seem to be ready.

 

Non-invasive brain stimulation for Patient with Autism A Systematic Review and Meta-Analysis

Objective: To comprehensively evaluate the efficacy of non-invasive brain stimulation (NIBS) in patients with autism spectrum disorder (ASD) in randomized controlled trials (RCT),providing reference for future research on the same topic.

Methods:Five databases were searched (Pubmed,Web of science,Medline,Embase and Cochrane library) and track relevant references,Meta-analysis was performed using RevMan 5.3 software.

Results: Twenty-two references(829 participants) were included. The results of meta analysis showed that, NIBS had positive effects on repetitive and stereotypical behaviors, cognitive function and executive function in autistic patients. Most of the included studies had a moderate to high risk of bias, Mainly because of the lack of blinding of subjects and assessors to treatment assignment, as well as the lack of continuous observation of treatment effects.

Conclusions: Available evidence supports an improvement in some aspects of NIBS in patients with ASD. However, due to the quality of the original studies and significant publication bias, these evidences must be treated with caution. Further large multicenter randomized double-blind controlled trials and appropriate follow-up observations are needed to further evaluate the specific efficacy of NIBS in patients with ASD.


Unfortunately, the Chinese have concluded that most of these studies are not reliable. So no laser for me to go out and buy just yet.

No need to dent your bank balance with the next therapy.  We are back to one of the world's most prescribed and therefore affordable drugs, its Simvastatin (Zocor). 

There is masses of information in this blog about the potential to treat sub-types of autism with Atorvastatin, Simvastatin or Lovastatin. They are each slightly different.

 

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model 

Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway. 

Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting. 

Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p < 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats. 

Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

  

Conclusion

What is the conclusion? Well, I could say give up reading the new research and just read my old posts.  It seems you are not going to miss very much.

Of course, back in the real world, it is true that things do take time to change and after a few decades the leap might be taken from the research to the doctor’s office.

There already is plenty of research on the causes of autism and what steps can be taken by those who want to treat aspects of it.  It is far from a complete picture, but it is enough to get started.  There are no guarantees of success, but if you want 100% certainty you will wait forever.