Agmatine - a Magic Bullet in Clinical Neuroscience?

Today’s post is about Agmatine, a naturally occurring metabolite of the amino acid arginine, which is referred to in recent studies as both a “magic bullet” and a “magic shotgun”.

Normally when things sound too good to be true, you do need to be rather suspicious, but our reader Tyler has already been trialing Agmatine over the summer months and he continues to be a big believer.

As we will see in this post Agmatine has multiple different effects and while this is often the case with drugs and gives them both good and bad effects, in the case of Agmatine this ability to affect multiple targets is put forward as an advantage.

NAC, the antioxidant now widely used in autism, also has numerous beneficial effects and can even reverse propionic acid induced autism. I think we can call NAC a silver bullet.

You will recall that amino acids are the building blocks of proteins. Nine amino acids are called essential for humans because they cannot be produced by the human body and so must be taken in as food. Arginine is classified as a conditionally essential amino acid, depending on the developmental stage and health status of the individual. Preterm infants are unable to synthesize or create arginine internally, making the amino acid nutritionally essential for them.

Agmatine

Agmatine was discovered in 1910.  It is a chemical substance which is naturally created from the chemical arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably neurotransmitter systems, ion channels, nitric oxide (NO) synthesis and polyamine metabolism.

Many of agmatine’s effects are potentially relevant to neurological conditions like autism. My initial thought was that with so many different effects, how likely would it be that the overall effect would be positive?

• Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.
• Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca²⁺ channels, and acid-sensing ion channels (ASICs).
• Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system.
• Nitric oxide (NO) synthesis modulation. Differential inhibition by agmatine of all isoforms of NO synthase (NOS) is reported.
• Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme.
• Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation.
• Matrix metalloproteases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9.
• Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation.
• NADPH oxidase. Activation of the enzyme leading to H₂O₂ production.

Different effects are likely to predominate at different doses, as with many drugs.

Of the above effects many are implicated in autism.

Nicotinic, NMDA, and serotonin receptors are all deeply implicated in autism.

All the above ion channels including ASICs, which have not yet been covered in this blog, are implicated in autism. Acid Sensing Ion Channels (ASICs) are implicated in autism via the genetic research and surprisingly brain pH is disturbed in many neurological conditions. 

“Maintaining the physiological pH of interstitial fluid is crucial for normal cellular functions. In disease states, tissue acidosis is a common pathologic change causing abnormal activation of acid-sensing ion channels (ASICs), which according to cumulative evidence, significantly contributes to inflammation, mitochondrial dysfunction, and other pathologic mechanisms (i.e., pain, stroke, and psychiatric conditions). Thus, it has become increasingly clear that ASICs are critical in the progression of neurologic diseases.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449961/

Nitric oxide is relevant to autism and any vasodilatory effect might be helpful to those with reduced cerebral blood flow. This benefit potentially goes beyond those with vascular dementia and may enhance memory and cognition in some.

It the effect on nitric oxide which body builders think gives them a benefit from taking Agmatine.

Polyamines and spermidine in particular are involved in autophagy, which is the intra-cellular garbage disposal service. When autophagy is impaired, as in many neurological conditions, this accumulating garbage gets in the way of cellular function. We already know that improving autophagy is one method of combating cognitive decline. We know that autophagy is impaired in autism.

NADPH oxidase and nNOS (Neuronal nitric oxide synthase) redox signaling cascades interact in the brain to affect both cognitive function and social behavior. I am not sure whether Agmatine will have a good or bad effect.                                                                  

The Research

I would be the first to point out that the Agmatine research is not like the high powered research we see from the scientists on this blog’s Dean’s List, but that does not mean the Agmatine may not be highly beneficial.  It is more like the copious research on antioxidants.

Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? 

Agmatine, the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α₂-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague. The purification and biochemical characterization of natural mammalian arginine decarboxylase and agmatinase still are open issues. Nevertheless, the agmatinergic system is currently one of the most promising candidates in order to pharmacologically interfere with some major diseases of the central nervous system, which are summarized in the present review. Particularly with respect to major depression, agmatine, its derivatives, and metabolizing enzymes show great promise for the development of an improved treatment of this common disease.                                                                                                                         

Agmatine: Clinical applications after 100 years in translation

Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.

“Agmatine is now considered to be capable of exerting modulatory actions simultaneously at multiple target sites, thus fitting the therapeutic profile of a ‘magic shotgun’ for complex disorders”

  

Mitochondrial protection 

Agmatine has been shown to exert direct protective effects on mitochondria at nanomolar concentrations. It has also been shown

to alleviate oxidative stress-induced mitochondrial swelling, possibly by acting as a free radical scavenger, and prevent Ca2+-dependent induction of mitochondrial permeability transition (MPT) by modulating itochondrial membrane potential and NF-kappaB activation and references therein). Importantly, these effects are implicated in apoptotic cell death. Therefore, mitochondrial protection is considered essential in contributing to the general cytoprotective effects of agmatine in various bodily systems and, thus, to its beneficial effects in a spectrum of disease models. Of special interest is a potential for agmatine utility in neurodegenerativediseases where mitochondrial malfunctions have been implicated (e.g., Parkinson’s disease).  

Drug development: therapeutic potential outweighing risks 

There remain constraints on progress towards practical development of agmatine as a drug. First, the lower level of protection against commercial competition afforded by ‘usage’ patents for new indications of known compounds, such as agmatine with its long known methods of chemical synthesis, is viewed as being much less lucrative by drug developers than that provided by ‘composition of matter’ patents for new chemical entities. Second, although research of new compounds to modulate endogenous agmatine metabolism holds promise, it is rudimentary and remains speculative. Third, even though agmatine, as a naturally occurring substance, has been developed and introduced to the dietary supplement and nutraceutical market, nutraceutical products in the USA fall under the ‘Dietary Supplement Health and Education Act (DSHEA)’, which forbids promotion of nutraceuticals for the treatment, cure, or prevention of any disease. Similar regulatory restrictions exist worldwide and severely limit the advertising of nutraceuticals to the medical market. 

Despite these constraints, compelling evidence indicates the therapeutic potential of agmatine for a spectrum of diseases. A summary of the advances made and the gaps still remaining for future research are indicated in Table 2. Although comparative efficacy studies with presently available drugs are still required, the broad safety profile of agmatine has been established with no serious adverse effects, either as a stand-alone or as an add-on treatment. This should be a paramount advantage when compared with most existing drugs and certainly to combination therapy.

Moreover, its general cytoprotective actions suggest that agmatine should be considered not only as a curative, but also as a preventive therapeutic.

Tyler’s Comments

Tyler’s comments in this blog regarding the use of Agmatine suggest that at different doses, the effect does indeed vary. At lower doses there can be negative effects like anxiety and aggression, but at 1.2 g (in a 50kg boy) the main affect is enhanced cognition.

https://epiphanyasd.blogspot.com/2017/06/modulating-wnt-signaling-in-autism-and.html?showComment=1498387748575#c1577296526823968689

https://epiphanyasd.blogspot.com/2017/08/music-for-autism-acquired-taste.html?showComment=1503773056629#c1943101059018652346

In treating strictly defined autism, cognitive function is often the most important target, unlike in milder forms of autism.

Tyler’s main purpose for trialing Agmatine was that it is thought to normalize the opioid system in the brain, via its action on adrenoreceptors.  Then came a mouse study in the valproic acid model of autism.

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

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD. 

in addition to a study in OCD:-

AGMATINE AMELIORATES SOCIAL ISOLATION INDUCED OBSESSIVE-COMPULSIVEBEHAVIOR IN MICE

Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. Obsessive-compulsive disorder is classified as an anxiety disorder under DSM-IV-TR guidelines. In OCD, the levels of serotonin and nitric oxide decreased; whereas levels of dopamine and glutamate increased in brain. Environmental conditions such as isolation from social surroundings lead to anxiety and increased level of aggression. The present study was designed to examine the effect of agmatine in social isolation induced obsessive-compulsive behavior on marble burying behavior and locomotor activity. Agmatine (20, 40 and 80 mg/kg, i.p.) was administered in different groups of mice; activity was observed 30 min after dosing. Acute treatment of agmatine (40 and 80 mg/kg, i.p.) significantly reduced marble burying behavior. Moreover, hyperlocomotion was observed in socially isolated animals and agmatine was found to attenuate the same without affecting basal locomotions. In conclusion, agmatine effectively decreases social isolation induced obsessive-compulsive behavior in mice

I think it is fair to say that we do not know which mode(s) of action are in effect at this dosage. Clearly dosage is very important.

Given the importance of maximizing cognitive function in those with some cognitive dysfunction, Agmatine is clearly well worthy of further investigation.

Conclusion

Agmatine does indeed seem to have to potential to benefit some people with neurological disorders.  Is it a magic bullet for everyone? I doubt it, but that is an unrealistic expectation for any drug.

If it can improve cognition, even in a minority of autism, that would be a significant finding. Hopefully other readers of this blog will have the same positive experience as Tyler.  It will be interesting to find out how the effective dose varies. Depending on which brand you use, 1 teaspoon (5ml) of agmatine powder contains between 2.2 and 3.5 grams, which looks odd.  Probably best to weigh it to be sure.

Agmatine sulphate/sulfate is widely available in North America as a body builder’s supplement, but is banned in Europe. It was not banned for safety reasons, rather some odd EU rule that since it was not sold before 1997, it now needs to go through an approval process, that someone would have to pay for, before it can continue to be sold. Agmatine is not such an effective body building supplement to warrant anyone investing much in it. Hopefully the FDA will not ban it in the US.

Music for Autism? – an acquired taste, apparently

Today’s post is about music and music therapy.

A new study reports that music therapy does not improve autism symptoms.

In an earlier post we saw that singing reduces the level of your stress hormone cortisol; this was based on testing adults in a choir, so not music novices.

Music has actually been shown to do much more than just reduce your level of stress, it can actually affect the expression of your genes, but only in those who are “musically experienced”; in people with little experience of music it does nothing. 

The effect of listening to music on human transcriptome

Although brain imaging studies have demonstrated that listening to music alters human brain structure and function, the molecular mechanisms mediating those effects remain unknown. With the advent of genomics and bioinformatics approaches, these effects of music can now be studied in a more detailed fashion. To verify whether listening to classical music has any effect on human transcriptome, we performed genome-wide transcriptional profiling from the peripheral blood of participants after listening to classical music (n = 48), and after a control study without music exposure (n = 15). As musical experience is known to influence the responses to music, we compared the transcriptional responses of musically experienced and inexperienced participants separately with those of the controls. Comparisons were made based on two subphenotypes of musical experience: musical aptitude and music education. In musically experienced participants, we observed the differential expression of 45 genes (27 up- and 18 down-regulated) and 97 genes (75 up- and 22 down-regulated) respectively based on subphenotype comparisons (rank product non-parametric statistics, pfp 0.05, >1.2-fold change over time across conditions). Gene ontological overrepresentation analysis (hypergeometric test, FDR < 0.05) revealed that the up-regulated genes are primarily known to be involved in the secretion and transport of dopamine, neuron projection, protein sumoylation, long-term potentiation and dephosphorylation. Down-regulated genes are known to be involved in ATP synthase-coupled proton transport, cytolysis, and positive regulation of caspase, peptidase and endopeptidase activities. One of the most up-regulated genes, alpha-synuclein (SNCA), is located in the best linkage region of musical aptitude on chromosome 4q22.1 and is regulated by GATA2, which is known to be associated with musical aptitude. Several genes reported to regulate song perception and production in songbirds displayed altered activities, suggesting a possible evolutionary conservation of sound perception between species. We observed no significant findings in musically inexperienced participants.

  

Apparently there are about 7,000 music therapists in the United States and about 6,000 in Europe.  One of the target groups for these therapists is children with autism.

So should parents pay out their cash for music therapy classes?  Well a very recent large study carried out in nine countries by a team from Norway suggests you might not want to open your wallet.

I must say that I hold a different view and that this simplistic kind of research is rather unhelpful. 

From the research in this blog we know that people who develop a love of music express a measurable biological effect, which does indeed look beneficial.

How do you develop a love of music, or indeed dance? Well you have to be exposed to it and engage in it.

Music therapy is all about engaging in music.

Monty, now aged 14 with ASD, has been dancing almost since he was walking, in great part because his then assistant loved music.  Later on you can start to make your own simple music, later you can sing and eventually play an instrument.  This process takes years.  

Music therapy is just a start, years later you can be trampolining to Abba, lying in bed listing to classical music, or just playing the piano.  But it is a long road.

In the recent research they gave 5 months of music therapy to 364 children aged 4 to 7 and then tested their social skills using the Autism Diagnostic Observation Schedule (ADOS).  Their social skill score did not improve. I am not sure why they picked this variable to measure.

This is yet more flawed research, which will then be quoted as fact by others.

You could make a study on teaching judo to kids with autism. I think you would find after 5 months it did not improve their social skills, but those who continue for 5 years might benefit considerably, versus those sat on the sofa watching videos on their iPads.

Clearly not everyone likes music, or indeed judo. Many kids with more severe autism have little interest in anything and so they need a lot more encouragement than typical kids.

The only way to find out if children can develop an interest in music, sport or anything else is to expose them to it at a young age. This is all music therapy is supposed to be, it is not meant to be a cure for anything. 

Music therapy may not lead to big benefits for kids with autism

Researchers found that children with ASD in nine countries scored similarly on a test of their social skills whether or not they had received the music therapy.

"Music therapy - like many other interventions that have been suggested - does not improve autism symptoms," said senior author Christian Gold, of the Grieg Academy Music Therapy Research Center and Uni Research Health in Bergen, Norway.

ASDs are developmental disorders that can lead to social, communication and behavioral challenges. The U.S. Centers for Disease Control and Prevention estimates that one in 68 children in the U.S. has been diagnosed with an ASD.

The anecdotal link between music and ASD goes back many years, Gold and colleagues write in JAMA. During music therapy, a person helps a child spontaneously make music through singing, playing and movement.

There are about 7,000 music therapists in the United States and about 6,000 in Europe, the researchers write.

For the new study, the researchers recruited 364 children ages 4 to 7 years from 10 treatment centers between 2011 and 2015. The centers were in Australia, Austria, Brazil, Israel, Italy, Korea, Norway, the UK and the U.S.

All of the children received the usual care a child with ASD would receive in their region, but half of the children were randomly assigned to also get music therapy.

Usual care could range from early intensive behavioral interventions, to speech and language therapy, to sensory-motor therapies and medications, Gold told Reuters Health by email.

"Music therapy is also among the interventions that have been recommended when it is available," he said. "Some parents who are frustrated with behavioral interventions may experience it as bringing back the joy of being with their child in a natural way."

After five months of therapy, the researchers did not find a difference between the two groups of children on a measure of social skills.

Gold said parents should continue to pursue music therapy if they feel it's a good match for their children, but don't expect it to be a so-called treatment.

The article below is quite a good one:

 Study casts doubt on music therapy for kids with autism

The study itself:

Music Therapy for Children with Autism Spectrum Disorder

In this issue of JAMA, Bieleninik and colleagues¹ present the results of a large, well-designed, multicenter randomized clinical trial (RCT) of improvisational music therapy for young children with autism spectrum disorder (ASD). Music therapy is “a systematic process of intervention wherein the therapist helps the client to promote health, using musical experiences and the relationships that develop through them.”² Among 364 children aged 4 to 7 years, over 5 months, the mean scores on the Autism Diagnostic Observation Schedule (ADOS), social affect domain, decreased from 14.08 to 13.23 among children randomized to improvisational music therapy and from 13.49 to 12.58 among those randomized to enhanced standard care, a mean difference in change scores of 0.06 (95% CI, −0.70 to 0.81), with no significant differences between groups.

  

How Much Music?

I think you need music lessons twice a week to have a meaningful impact and, as with all therapies, you need more practice at home.  Most kindergartens have music and dance as part of their activities. Taken together it is not so hard to get quite a lot of exposure to music at a young age. Then, if the child really likes music, you just keep going.  

Conclusion

Is music therapy a quick fix for autism? Definitely not.

Is music therapy a fun way to engage many young children with autism? The recent research does not say so, but it is clear that many people, with all levels of autism severity, can enjoy music and participate in it.

I think we should put music alongside sport, as a useful activity that young children should be encouraged to engage in.   It can be a struggle to get some people with autism to engage in anything, which is where a music therapist comes in.

Is it worth the investment in time and money? That all depends on the child and the therapist. Buying a piano, 7 years ago, was certainly one of my better investments; but you do also need a lot of lessons.  The end result is someone with a genuine love of many kinds of music and I expect he is now in the cortisol lowering, gene expression modifying category of the musically experienced.

Five months of unspecified music therapy may not be enough to see results and quite possible those results are not increased sociability anyway.

Viruses, Bacteria, Fungi, Parasites and Altered Gene Expression, Relevant to Autism

Today’s post started life as a review of how some viruses affect gene expression and may help cause, or just trigger flare-ups in, some neurological disorders ranging from autism to MS (multiple sclerosis). 

Some people with autism are treated with anti-viral drugs and, anecdotally, some do respond well.  This is not yet an area with hard facts and definitive clinical trials.  

It is actually better to first take a few steps back and consider how all microorganisms can play a role in human health by modifying the gene expression of the host (which is you).  There are four broad categories of microorganism.

Each type of microorganism can be countered by a matching category of pharmaceutical.

·        Antibacterials/antibiotics for bacteria

·        Antifungals to kill or prevent further growth of fungi

·        Antivirals to minimize (but often not eradicate) viruses

·        Antiparasitics to kill parasites  (protists)

All of the above categories of microorganism can affect the expression of multiple genes. By either up or down-regulating important genes at critical times during development, long lasting effects can be created, or there may be just transient effects.

Changes in gene expression likely play a role in many neurological conditions and in particular in what I call “flare-ups”, for example in autism, PANS, PANDAS and indeed schizophrenia.

Not all changes in gene expression are bad. The TSO parasites that do seem to help some people’s autism, by down regulating their immune response, very likely are modifying the host’s gene expression, which then reduces their immune response. This is the mechanism developed by the parasite to protect itself from the host (you) and ensure it is not eradicated.

Steroids affect the expression of multiple genes. When a bacteria of virus triggers PANDAS/PANS the positive effect of steroid therapy may well be by “resetting” the expression of certain important genes.  Here again, even though PANDAS/PANS is now treated clinically in the US, much remains unknown.

For those interested, earlier this summer revised treatment guidelines were published for PANDAS/PANS.

In "Part I–Psychiatric and Behavioral Interventions," Margo Thienemann, MD, Stanford University and coauthors present consensus guidelines for treating the psychiatric and behavioral symptoms of children with PANS/PANDAS. Symptom improvement is aimed at decreasing suffering, improving functioning, and making it easier for the children to adhere to therapeutic interventions.

In "Part II–Use of Immunomodulatory Therapies," Jennifer Frankovich, MD, and coauthors provide recommendations to help guide the use of therapies targeting the neuroinflammation and post-infectious autoimmunity that are common in PANS-PANDAS.

In “Part III–Treatment and Prevention of Infections," Michael Cooperstock, MD, MPH, University of Missouri School of Medicine (Columbia) and coauthors representing the PANS PANDAS Consortium, present a consensus guideline for managing the infection components of these neuropsychiatric conditions.

There is research on what virus/bacteria affects which specific gene, but this area of science is in its infancy.

MS (Multiple Sclerosis) a condition that features faulty remyelination, is likely a much simpler condition than autism and yet nobody knows for sure what causes it. It has been suggested that a virus may be the trigger of at least some types of MS, but researchers are decades away from proving anything. So when it comes to microorganisms and autism, it is mainly a case of speculation and the odd N=1 case study. 

Viral triggers of multiple sclerosis 

The relationship between infections and autoimmune diseases is complex and the mechanisms by which infectious pathogens could trigger MS are likely dynamic, i.e., they might change over time and not be mutually exclusive. Epidemiological observations indicate that viral infections could contribute to MS development not only as triggers of disease exacerbations but also as etiological agents, i.e., long before the disease becomes clinically apparent. The two- to three-folds increased risk of developing MS among individuals with history of IM compared with subjects who acquired EBV without symptoms, the almost universal seropositivity for EBV in adults and children with MS, and the steep and monotonic increase in MS risk with increasing titers of antibodies to EBV in apparently healthy adults could suggest that EBV infection is causally linked to MS development. The mechanisms responsible for this association are far from understood. Moreover, the incidence of IM in Western countries (≥ 5%)  exceeds the prevalence of MS in comparable populations (0.1%) by far (more than 50-fold) suggesting that yet unidentified genetic and/or additional environmental factors determine whether symptomatic EBV infection indeed predisposes to MS.

Although one particular MS-causing agent might still be discovered, current data suggest that multiple infections along with noninfectious environmental factors trigger the development of MS. These factors are likely ubiquitous, i.e., highly prevalent in the general population, and they require a permissive genetic background that predisposes for MS development. Future studies investigating infectious pathogens in a complex and heterogenous disease such as MS will benefit from careful and detailed clinical, pathological, and neuroimaging-based patient characterizations and from reproducibility in different study populations. In addition, novel humanized animal models of autoimmune diseases that are simultaneously permissive for viral pathogens which usually infect only humans  should allow investigation of specific aspects of host–pathogen interactions during autoimmune CNS inflammation in vivo. The integration of these data might eventually allow us to better define the role of viruses in the etiology and pathogenesis of MS and how virus–host interactions could be targeted for MS therapy.  

Hidden herpes virus may play key role in MS, other brain disorders

The ubiquitous human herpesvirus 6 may play a critical role in impeding the brain's ability to repair itself in diseases like multiple sclerosis. These findings may help explain the differences in severity in symptoms that many people with the disease experience

What is still not fully understood is the relationship between the extent of the viral infection in the brain and the severity of diseases like multiple sclerosis and other demyelinating diseases such as leukodystrophies and Vanishing White Matter disease. For example, do the number of infected cells need to reach a certain threshold before OPC function is impeded? Are individuals who have congenital HHV6 more vulnerable to severe forms of these diseases?

"More research is needed to understand by which mechanisms the virus impedes the function of OPCs and what impact this has on the progression of these diseases," said Mayer-Proschel. "But it is clear that HHV6, while not necessarily the cause of demyelinating diseases, is limiting the ability of the brain to repair damage to myelin thereby potentially accelerating the progression of these diseases."  

Mainstream and “Alternative” Research  

Not all published research fits with the current mainstream scientific consensus. The mainstream is clearly moving towards the realization that all kinds of things can affect gene expression. One currently fashionable area is the gut microbiota, as in this article:-

Gut's microbial community shown to influence host gene expression

Some researchers develop hypotheses that go much further, like this one regarding autism’s elder brother, schizophrenia.

Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses and Pathogens and Dependent on Genes 

Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

And this one by the same author:-

Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders.

Herpes simplex virus 1 (HSV-1) can promote beta-amyloid deposition and tau phosphorylation, demyelination or cognitive deficits relevant to Alzheimer's disease or multiple sclerosis and to many neuropsychiatric disorders with which it has been implicated. A seroprevalence much higher than disease incidence has called into question any primary causal role. However, as also the case with risk-promoting polymorphisms (also present in control populations), any causal effects are likely to be conditional. During its life cycle, the virus binds to many proteins and modifies the expression of multiple genes creating a host/pathogen interactome involving 1347 host genes. This data set is heavily enriched in the susceptibility genes for multiple sclerosis (P = 1.3E-99) > Alzheimer's disease > schizophrenia > Parkinsonism > depression > bipolar disorder > childhood obesity > chronic fatigue > autism > and anorexia (P = 0.047) but not attention deficit hyperactivity disorder, a relationship maintained for genome-wide association study data sets in multiple sclerosis and Alzheimer's disease. Overlapping susceptibility gene/interactome data sets disrupt signalling networks relevant to each disease, suggesting that disease susceptibility genes may filter the attentions of the pathogen towards particular pathways and pathologies. In this way, the same pathogen could contribute to multiple diseases in a gene-dependent manner and condition the risk-promoting effects of the genes whose function it disrupts.

Back to Autism

As we have seen previously in this blog, autism is usually polygenic, meaning very many different genes are affected. This does not mean that anything is necessarily defective in those genes, it just means those genes are either over or under-expressed, this means you end up with either too much, or too little, of whatever that gene makes.

So for a polygenic condition, where in one person hundreds of your 22,000 individual genes are likely over or under-expressed, we really do not want anything to come along and further miss-express critical genes.

Many genes are inter-related and so miss-expression of one can trigger a wave of further effects. This can be either good or bad.

The science is still in its infancy, so it will be many decades before it is translated into medicine, but we can certainly already say what may be happening.

The interactome is a relatively new word to describe the whole set of molecular interactions in a particular cell.

 For example, the well-known bacteria H.pylori that can cause stomach ulcers:- 

The protein-protein interaction map of Helicobacter pylori 

Over 1,200 interactions were identified between H. pylori proteins, connecting 46.6% of the proteome.

Just this one common bacterium affects half of the entire set of proteins expressed by a genome (the so called proteome).

So we should not be surprised if some bacteria or viruses have a bad, or indeed good, effect on autism.

This also bring us back to the idea of the holobiont and hologenome, which was introduced in an earlier post. The idea is that what really matters in human health is not just your genome, but the totality of what surrounds you, so that means everything living in you, on you and around you. That includes bugs, bacteria and also those of your pet dog.

All of these factors influence how your genes are expressed. During evolution your body has got used to things and if you make rapid changes, you may indeed upset the balance. So while chlorinating water may have an overall good effect, by killing all those bacteria your body had been expecting, there may be some negative effects. Humans evolved living close to animals, be it dogs or farm animals. We saw earlier that pregnant mothers who live with pets produce children with a lower incidence of asthma.

We also reviewed the hygiene hypothesis, which basically says that a bit of dirt is good for you.

So this post, rather than narrowing things down, really broadens them out.  Everything affects everything.  If you rock the evolutionary boat, don’t be surprised if strange things happen.

Taking Somali refugees to live in Sweden increased their incidence of autism. Is that really a surprise? Recall the Somali autism clusters in Sweden and San Diego.

Apparently, the Amish in the US have a low prevalence of autism. Is that really a surprise?  One reader recently suggested sending autistic people to live with the Amish, as a therapy. The possibly effective therapy would have been to send the parents to live with the Amish for a couple of years before the child was born.

So perhaps we should consider much autism, and indeed conditions like asthma, as collateral damage from modern living?  Life expectancy has risen, infant mortality has been greatly reduced, but the downside is that we now have much more autoimmune disease and that includes autism.

Autism and Microorganisms

Now back to autism and the four categories of microorganism.

Can parasites cause autism? Actually we know they can; for example cerebral malaria can result in it. But how often is this case? Probably very rarely.

Can fungi cause autism? Perhaps, but we know from many examples (including in the comments on this blog) that some fungi can make autism worse.  Is the fungus candida albicans growing in the intestines really an issue in most autism? I seriously doubt it, but oral thrush/candidiasis caused by inhaled steroids does seem to make autism worse and is reversible by removing the fungus. The effect seems more likely to be from the candida than the steroid, since inhaled steroids only mildly enter the bloodstream.

Can bacteria cause autism? Well streptococcus bacteria can cause OCD and cognitive impairment (PANDAS).

Can a virus cause autism? Antonio Persico, one of the more serious autism researchers, has suggested that some autism may be caused by polyomaviruses transmitted at conception from father to mother.

https://spectrumnews.org/news/could-a-virus-cause-autism/

Can the rubella virus cause autism? Some serious people do see a possibility, even in people who have been vaccinated.

Does Rubella Cause Autism: A 2015 Reappraisal? 

These both remain controversial hypotheses; but can viruses cause flare ups in autism, later in life? This is also controversial, but I think quite plausible.  It all depends which genes the virus causes to get miss-expressed.

Enough is known to say that odd changes in autism may potentially be triggered by the appearance of specific types of microorganism, but quite possibly most microorganisms have little, or no, negative effect in most people. So it is not a case of all viruses/bacteria will make autism worse, but it is likely true that some may have the potential to do so.

In trying to figure out possible causes of autism flare-ups, due consideration should be given to microorganisms.  This is another case of personalized medicine, with all its potential pitfalls.

The big risk is potentially becoming obsessed with non-existing bacteria, viruses, fungi or parasites.  

Back to Antivirals and Autism 

Finally we come back to where the original idea for this post came from; is there any basis of the use of antiviral drugs to treat autism?

DAN-type doctors do prescribe the antiviral drugs Valtrex, Famvir or Acyclovir.

https://www.tacanow.org/family-resources/diagnosing-and-treating-viral-infections-in-asd/

Antiviral drugs do not destroy their target virus they just inhibit its development.

Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses, the hepatitis B and C viruses, and influenza A and B viruses.

You identify a virus by looking for antibodies to that specific virus in the blood. You can test for antibodies that suggest if the infection is new and active, called IgM antibodies and you can test for antibodies that show the infection occurred sometime in the past, called IgG antibodies.

You would need to know which virus to test for, the common ones are:-

HSV 1:  Herpes Simplex Virus 1 causes canker sores in the mouth

HSV 2: Herpes Simplex Virus 2 causes genital herpes.

HHV 6: Human Herpes Virus 6 is commonly known as Roseola virus

EBV: Epstein-Barr Virus, causes the illness known as infectious mononucleosis

Measles

Rubella  

Herpes virus may be a trigger for autism

“We’re not saying that HSV-2 is responsible for infecting the [fetal] brain and causing autism,” stresses senior author Ian Lipkin, an infectious disease expert and epidemiologist at Columbia. Indeed, fetal infection with HSV-2 is so serious that it frequently leads to miscarriages or stillbirths. Rather, Lipkin suspects that HSV-2 is just one among many environmental insults that, when they arrive at a vulnerable point in fetal development in women predisposed to damaging reactions, may trigger ASD in the fetus.” 

Prevalence of Herpes Simplex Virus 1 and 2 Antibodies in Patients with Autism Spectrum Disorders 

Conclusion: Rate of contact with HSV1 and HSV2 assessed by the mean of detection of specific antibodies was similar between children with ASD and healthy controls.

Prevalence of HHV-6 and HHV-8 Antibodies in Patients with Autism Spectrum Disorders

Conclusion: Levels and seropositivity rate of antibodies to HHV-6 and HHV-8 do not differ between children with ASD and controls.

Prevalence and titre of antibodies to cytomegalovirus and epstein-barr virus in patients with autism spectrum disorder

CONCLUSION: Titre and seropositivity rate of antibodies to CMV and EBV are similar between children with ASD and healthy controls.

Valtrex 

Valtrex seems to be the antiviral most commonly prescribed in autism.  This is an off-label use, meaning Valtrex is not approved to treat autism.  Valtrex is active against most species in the herpesvirus family. In descending order of activity:

• Herpes simplex virus type I (HSV-1)
• Herpes simplex virus type II (HSV-2)
• Varicella zoster virus (VZV)
• Epstein–Barr virus (EBV)
• Cytomegalovirus (CMV)

So we might assume the people with autism who respond to Valtrex might have one of the above, or similar, viruses. Unless Valtrex has some other modes of action, unrelated to being an anti-viral, which remains a possibility. 

Mitochondrial Disease and Viral Infections

Since this post is already full of speculation, I will add some more. Some people say that their child’s mitochondrial disease was preceded by a viral infection, so how likely is it that a virus can trigger mitochondrial disease and then autism?  Again, this is not something anyone can prove, one way or the other, but it does look like your mitochondria are particularly vulnerable to viruses.

The virus will exploit the mitochondria to further its own development, perhaps in doing so, in some people with a pre-disposition, this triggers a process to chronic mitochondrial dysfunction.  Read the papers below for more on this subject.

Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. 

Viruses as Modulators of Mitochondrial Functions

Mitochondrial dynamics and viral infections: A close nexus

Highlights

Mitochondrial dynamics influences mitochondrial and cellular functions.

Mitochondrial dynamics is affected during viral infections.

Viruses exploit mitochondrial dynamics and mitophagy to benefit infectious process.

Virus-altered mitochondrial dynamics determines the outcome of infection.

Disruption of mitochondrial dynamics promotes viral pathogenesis.

If a virus can trigger mitochondrial disease, as we have seen a vaccination can, is there any possible merit in using antivirals years later?

Is there merit treating regressive autism, which is likely to be mitochondrial disease, immediately with antiviral drugs?

Is there merit treating autism flare-ups, that do not respond to PANDAS/PANS therapies, with antiviral drugs?

Is there merit treating MS (multiple sclerosis) immediately on diagnosis with antiviral drugs? Would MS flare-ups respond to antivirals?

My take

If I was to develop MS tomorrow, given there is currently no cure, I think I might want to try an antiviral, just in case it might actually do some good.

My son with classic autism did have a PANDAS-like regression last year, with sudden onset OCD and strange verbalizations. It all went away after a couple of weeks, having been treated as a PANDAS flare-up, as documented in an old post on this blog. If after a viral infection he developed a sudden onset regression I would certainly reread this post.

Readers of this blog with a clear case of mitochondrial disease might want to check for the commonly implicated viruses, since if one was never suppressed this might be something to consider.

So do antivirals have a place in treating autism?  There is no hard evidence to support their use, but I would not at all be surprised if a minority do genuinely benefit. I think the most likely group might be those who have a sudden regression from near typical. As with PANDAS/PANS, the sooner the treatment commences, the better the likely outcome. 

Could antivirals help control flare-ups that can occur in those already with autism? They could well help; ideally you would confirm the presence of the virus first.   

Conclusion

I recently watched an expert clinician talking about irritable bowel syndrome (IBS); he was very open about his opinion that science likely only understands about 30% of the disorder. When it comes to autism I think science may be only at the 10% mark. As a result you have to be very careful about saying anything definitive.

We know that very many things contribute to the prevalence of autism.  It looks more than likely that viruses, bacteria, fungi and parasites may, on occasion, play a role in some people’s autism.

But, just like we know that in some people vaccination can trigger mitochondrial disease and result in an autism diagnosis, this does not mean it is a common cause of autism. Vaccinations have saved hundreds of millions of lives, but it has long been known that they can have side effects and that is why there is a large industry-funded compensation scheme in the US.

So while parasites can in some circumstances lead to autism, this does not mean feeding bleach to children with autism is a clever idea. Nor does filling them with antibiotics to treat a non-existing bacteria.

You can see why mainstream medicine is not eager to treat autism.

Nonetheless, applying that meagre sounding 10% of understanding can yield results, when applied with caution.