Nitric Oxide (NO), Arginase and Endothelial Dysfunction in Autism

Endothelial dysfunction is not something people associate with autism. It is something I have covered previously in this blog and if you search on Google my post is about all you will find.

Endothelial dysfunction is acknowledged to be very important in diabetes, which is characterized by ROS (reactive oxygen species), reduced NO (nitric oxide) , reduced eNOS (endothelial nitric oxide synthase) and too much Arginase. There is also Peroxynitrite (ONOO⁻), an ion we have encountered before.

In autism we do already know from the research that VEGF (Vascular endothelial growth factor) is disturbed and there will be a post on that.

So when you put it all this together, it is odd that nobody has researched endothelial dysfunction and autism.  When I find something like this, my fallback is always schizophrenia. What about Endothelial Dysfunction and Schizophrenia? Sure enough, there is plenty of research on the subject, like this paper.

Microvascular dysfunction in schizophrenia: a case–control study

We tested the hypothesis that subjects with schizophrenia have impaired endothelial function.

Our findings suggest that a diagnosis of schizophrenia is associated with impaired microvascular function as indicated by lower values of VTI, irrespective of many other clinical characteristics. It might be an early indicator of cardiovascular risk in schizophrenia, and might help to identify high-risk individuals.

Endothelial Dysfunction does ultimately cause all kinds of problems in later life.  What is relevant to this blog is the potential neurological benefit of improving endothelial function in younger people, if any.

We need to recall that historically there have been very few older people with more severe autism; they did not live to the age when typical problems caused by endothelial dysfunction become apparent. 

Overlapping causes of Endothelial Dysfunction

The interesting question is just how many of the possible causes of endothelial dysfunction occur in autism. 

So far the following factors seem to apply to autism:-

·        Oxidative stress (ROS)

·        Reduced eNOS and nitic oxide (NO)    

·         VEGF (Vascular endothelial growth factor) is disturbed

·         Even estrogen deficiency can play a role and this is reduced in autism

People with autism who use calcium folinate (Leucoverin) are already quenching  Peroxynitrite (ONOO⁻) another factor in Endothelial Dysfunction.                                                               

Is Arginine/Arginase disturbed in Autism?

One well known anomaly in diabetes is a high level of an enzyme called Arginase, resulting in reduced production of nitric oxide (NO) in endothelial cells.

Here again we have to revert to looking at schizophrenia, as the closest thing to autism. Here there are no surprises. 

Altered brain arginine metabolism in schizophrenia.

Previous research implicates altered metabolism of l-arginine, a versatile amino acid with a number of bioactive metabolites, in the pathogenesis of schizophrenia. The present study, for we believe the first time, systematically compared the metabolic profile of l-arginine in the frontal cortex (Brodmann's area 8) obtained post-mortem from schizophrenic individuals and age- and gender-matched non-psychiatric controls (n=20 per group). The enzyme assays revealed no change in total nitric oxide synthase (NOS) activity, but significantly increased arginase activity in the schizophrenia group. Western blot showed reduced endothelial NOS protein expression and increased arginase II protein level in the disease group. High-performance liquid chromatography and liquid chromatography/mass spectrometric assays confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in the schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between l-ornithine level and the duration of illness. Moreover, cluster analyses revealed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. The present study provides further evidence of altered brain arginine metabolism in schizophrenia, which enhances our understanding of the pathogenesis of schizophrenia and may lead to the future development of novel preventions and/or therapeutics for the disease

Arginine metabolic pathways. l-arginine can be metabolized by NOS, arginase and ADC to form a number of bioactive molecules (see the Introduction for detailed description). We found increased levels of arginase activity, arginase II protein expression and agmatine tissue concentration (indicated by the red letters and arrows), and reduced eNOS protein expression and GABA level (indicated by the green letters and arrows) in the schizophrenia cases. ADC, arginine decarboxylase; BA8, Brodmann's area 8; eNOS, endothelial NOS; GABA, γ-aminobutyric acid; iNOS, inducible NOS; NO, nitric oxide; NOS, nitric oxide synthase; nNOS, neuronal NOS.  

It is of interest to note that the plasma agmatine level was increased over threefold in schizophrenic patients relative to healthy controls

The present study, interestingly, found an over 50% increase in arginase activity in BA8 accompanied by a significant upregulation of arginase II in the schizophrenia group. It is currently unclear how arginase changes in blood correlate with those in the brain tissue

Polyamines and agmatine have also been implicated in psychiatric disorders

L-Norvaline for Aspie1983?

One reader has raised issue of whether L-Norvaline would be a good idea.

L-Norvaline is an arginase inhibitor, used by body builders to increase nitric oxide.

L-arginine is used as a substrate by both nitric oxide synthase (NOS) and arginase to produce nitric oxide (NO) and urea, respectively.

If you inhibit arginase you shift the L-arginine over towards nitric oxide production.

People with diabetes and, as we saw above schizophrenia, have elevated levels of arginase. This will cause them to have a reduced level of nitric oxide. Reduced nitric oxide will contribute to Endothelial Dysfunction.

So it looks like L-Norvaline might well be beneficial in diabetes and schizophrenia.

L-Norvaline  might slow the conversion of ammonia to urea, if arginase was low to start with.  If arginase was elevated to start with you might expect no impact on the conversion of ammonia to urea.

Agmatine, Polyamines & L-citrulline 

Agmatine may already be elevated in schizophrenia, but it looks like a little extra can be beneficial in autism.

Polyamines can also be good for you if they increase autophagy. Which specific polyamine you want is an open question.

In the schizophrenia study L-citrulline is reduced. This makes sense because L-arginine has been shifted over towards  urea by elevated arginase. L-citrulline is a byproduct when nitric oxide (NO) is produced.

Perhaps unexpectedly, l-Citrulline is also a potent endogenous precursor of l-arginine. In a recent clinical study, l-citrulline supplementation dose-dependently increases plasma l-arginine levels in healthy human volunteers more effectively than equivalent doses of l-arginine itself.

Aspie1983 might not need to supplement L-citrulline, if he used L-Norvaline .

Altered brain arginine metabolism in autism?

I suspect Aspie1983 is not the only one with an altered brain arginine metabolism.

There appear to be many therapeutic options and they are all body building supplements because they will all increase nitric oxide (NO).

They will all improve Endothelial Dysfunction, which was the original subject of this post.

Conclusion

It certainly seems like Endothelial Dysfunction is present in some autism and that numerous established therapies should help.

We are already targeting oxidative stress with antioxidants and some people use calcium folinate that will target nitrosative stress.

The therapies that increase NO and/or eNOS include:-

·        Agmatine

·        L-arginine

·        L-citrulline

·        L- norvaline

·        Cocoa flavanols

·        Beetroot juice

·        L-taurine does increase eNOS and NO, but it is not clear how

There are products sold to body builders that include several of these and some clever additional ones.

Like this one, 12 grams made up of:-

1.   L-Citrulline

2.   L-Taurine

3.   Agmatine Sulfate 

4.   Glycerol Monostearate

5.   Dan-Shen, a Chinese cardio-protective herb that increases NO and also behaves like low dose aspirin

6.   Beetroot Powder

7.   L-Norvaline

8.   Hesperidin, a citrus flavonoid that increases NO

9.   Black pepper extract; piperine is known to affect NO release

Dan-Shen :- there are numerous clinical trials on Dan-Shen and its active ingredient. It has even been suggested to treat PANS/PANDAS.

These clinical trials include treating altitude sickness.

Hesperiden is found in oranges and indeed peppermint, but in oranges it is most abundant in the white inner part of the peel. Orange peel is a home remedy to lower cholesterol. Research shows that Hesperiden (and naringin) is a potent cholesterol lowering substance.

You would think that you can have too much of a good thing, that is too much endothelial nitric oxide; ask a body builder.

There is more to this subject, beyond the body builder’s science; the related areas to look at are angiogenesis and lymphangiogenesis. These are very much influenced by VEGF (Vascular Endothelial Growth Factor). In the next post we will see that there is evidence suggesting blood vessel growth can be unchecked in some autism resulting in unstable blood flow, not simply reduced flow.

So while the view from today’s post is that in autism there may be restricted blood flow, rather like in vascular dementia, the real situation is likely more complex.

We also have the issue of how the lymphatic system, that collects waste materials from the body (including the brain), may also be affected. With blood vessels there may be “too much growth” but in the case of lymphatic system there may be too little. This is all governed by VEGF.

We have already seen that autophagy and mitophagy are reduced in some autism and are a defining feature of Huntingdon’s Disease. Accumulation of waste products in the brain has consequences. Improved autophagy, possible via the same polyamines referred to in the earlier graphic, and improved lymphangiogenesis could be therapeutic. It appears that the brain flushes out waste products to the lymphatic system while you sleep; Alzheimer's is most prevalent in people who sleep very little.

Hypoperfusion in Autism Revisited

One old post from this blog has been going viral recently (3,000 views in one day, via Facebook) and it is quite relevant to a debate that has been going on in the comments about the potential merits and mechanisms of Hyperbaric Oxygen Therapy (HBOT). Two commenters are big fans of HBOT.

Hypoperfusion is reduced blood flow, which is found in some people with autism and also in people with some types of dementia  

Having reread my old post I would recommend it to those who are looking into the treatment of brain damage caused by ischemia. 

Brain Hypoperfusion in Autism & Cocoa

While much in neuroscience is extremely complicated, there are some pretty basic things to consider that are not. Adequate blood supply is one of the basic issues and is something that can be improved.

You can increase blood flow by reducing vascular resistance, which means reducing the work the heart has to do to circulate blood around the body. As you reduce this resistance, blood pressure will fall, but that does not mean the flow rate of blood has reduced, it just means it is circulating more freely.

You can measure cerebral blood flow and this is how researchers know that it can be abnormal in autism.

As I noted in the old post above, HBOT is one therapy proposed by some. Using an MRI you could establish with certainty if HBOT was effective in any particular individual, in regard to increasing cerebral blood flow.

I think there will be many ways to improve perfusion in an affected individual. Without a particular type of MRI you cannot really know for sure if your case of autism is one of these.

The dementia research pointed me towards cocoa flavanols, which seem to affect nitric oxide (NO), but do not directly produce it.

Nitric oxide (NO) is very important in the body and one of its roles is vasodilation (widening of blood vessels).

Some people believe that nootropic drugs work by vasodilation, i.e. more blood flow increases cognitive function.  I think that this is one of many possible ways to improve cognition, which will work in some people, but not others. 

To understand Nitric oxide (NO) you have to go a little deeper and look at eNOS (endothelial nitric oxide synthase), iNOS (inducible NO synthase) and nNOS (neuronal NO synthase). Nitric oxide can be very good for you, but it can also be very bad for you.  The short version is that Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) plays a protective role in maintaining vascular permeability, whereas NO derived from neuronal and inducible NOS is neurotoxic and can participate in neuronal damage occurring in ischemia.,

For a thorough explanation here is a highly cited paper:-

Nitric oxide synthases: regulation and function

Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins. 

Statins are already in my Polypill. Telmisartan seemed to be the most likely ACE inhibitor or ARB (angiotensin receptor blocker) to help some autism, when I reviewed them in a previous post. Telmisartan produced more singing, as does Agmatine (see below).

Now look at how NO is produced by eNOS:-

           https://en.wikipedia.org/wiki/Endothelial_NOS 

“In the vascular endothelium, NO is synthesized by eNOS from L-arginine and molecular oxygen, which binds to the heme group of eNOS, is reduced and finally incorporated into L- arginine to form NO and L-citrulline. The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO. In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled. In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.^”

BH4 (Tetrahydrobiopterin/Kuvan) is one of substances that comes up in autism research from time to time.  You would not want to be deficient in BH4 and if you have autism and BH4 deficiency you have a very obvious therapy.   

Biomarin’s Kuvan autism treatment faces reservations on the part of experts 

A good article, surprisingly from the UK Financial Times, which they ask not to be cut and paste, so I have not. Take a look.

If Kuvan lights up the brain, as Dr Frye suggested in the above FT article, I wonder what else can, in those people.  L-arginine might help, or perhaps its metabolite Agmatine, as used by our reader Tyler.

If you read the quite complicated paper below you will see that, in rats at least, Agmatine increases eNOS, while reducing  iNOS. 

You compare EC6 (experimental control after 6 hours) with Agm6 (Agmatine after 6 hours) and then EC24 with Agm24. 

Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain

Effects of eNOS and iNOS expression by agmatine treatment following transient global ischemia in rat hippocampus. Representative expressional levels of eNOS (A) and iNOS (C) at 6 h after agmatine treatment (100 mg/kg, i.p), and densitometric data (B, D). Data represent means±SD for n=5/NC, n=3/EC and Agm group per each time point. ^*

Cost

BH4/Kuvan/Sapropterin is rather expensive, but people do use it off-label in autism.  It is the only FDA-approved medication for Phenylketonuria (PKU) to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4-) responsive PKU.

http://www.biomarin.com/products/kuvan

PKU is one of those rare inborn errors of metabolism that lead to intellectual disability/MR and, not surprisingly, also autism. It is included in my Treatable ID tab at the top of every page.  The link will take you here  http://www.treatable-id.org/page36/Phenylketonuria.html

Agmatine is cheap and does have an almost immediate positive effect in some people with autism.

Do people who respond to BH4 respond to Agmatine and vice versa?

Agmatine does have many other modes of action, other than increasing eNOS and reducing iNOS.

I have been experimenting with Agmatine, and while Dr Frye suggests Kuvan can “light up the brain”, my impression of Agmatine brings the Energizer(US)/Duracell (Europe) Bunny to mind.

A daily dose of Agmatine is like having better battery in your toy bunny, at least in my house.  It is also associated with more singing.

Judging from Tyler’s comments perhaps he is seeing the same magnitude of effects that Dr Frye attributes to Kuvan.   

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.