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.