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Showing posts with label iNOS. Show all posts
Showing posts with label iNOS. Show all posts

Sunday, 24 September 2017

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. 


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:-


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.   


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. 




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.