Showing posts with label Hypoxia. Show all posts
Showing posts with label Hypoxia. Show all posts

Thursday, 7 March 2019

A Case Study Treating Adult Hypoxia with Clemastine - a potential treatment to promote myelin recovery in premature infants

I did think we had finished with Clemastine for a while, but a researcher reader of this blog sent me a very interesting recent case study about a man with brain damage caused by hypoxia (lack of oxygen) and we have the MRI brain scans showing how that damage was reversed by this OTC antihistamine. Hypoxia is often caused by carbon monoxide poisoning or in childbirth, if things get tangled up.

The researchers go on to suggest Clemastine treatment to promote myelin recovery in premature infants. In this case the graphics in the paper relate to mice, not humans, but are really impressive.
This means that what is called Ataxic Cerebral Palsy, which is caused by a lack of oxygen during birth might now have a treatment.
Some children with autism, including some discussed in the comments in this blog, appear to have suffered hypoxia during birth. This caused damage which resulted in symptoms of autism.  You would expect that damage to show up on the “right sort of MRI” in the same way as the adult male, below. Some of these children are reported by parents to respond to hyperbaric oxygen, even though it is carried out years after the hypoxia.

Findings in human DPHL case treated with clemastine. Axial FLAIR (fluid attenuated inversion recovery) at 1 (A), 2 (B), 6 (C), and 12 (D) months after injury in a human case of DPHL, showing MRI white matter abnormalities on FLAIR and diffusion weighted images, subtle at 1 month and striking at 2 months, parallel to patient’s worsening clinical course; white matter signal changes showed a periventricular/ deep white matter distribution with involvement of the corpus callosum (particularly splenium), with sparing of U-fibres. The patient was started on clemastine treatment at 2 months. At 6 months, MRI abnormalities in the white matter were partially normalized, showing fuzzy signal changes, unchanged at 12 months follow-up.

What I found interesting was the time delay, it was two months after the hypoxia that the man’s symptoms became really severe, but rather than being game over, the white patches in the month 2 MRI gradually fade away, after clemastine treatment started.
In my posts on autism and myelin, I pointed out that the problem appears to be re-myelination, which is the repair and maintenance of existing myelin. In autism you could consider it as “Friday afternoon myelination”, when the oligodendrocytes are thinking more about the weekend than your axons. In the man in the case study he already had plenty of myelin prior to his hypoxia, but the hypoxia affected his capacity to re-myelinate his axons.
The progressive cognitive decline with profound short-term memory loss, impaired executive function, and paucity of speech, psychomotor retardation, urinary incontinence and gait impairment was reversed.  The patient was seen in follow-up 5 months after his hypoxic event. His cognitive function had markedly improved and he was able to return to work.  All thanks to OTC clemastine and I think he should thank someone for reading the Multiple Sclerosis research on clemastine.
The researchers then looked in detail at a mouse model of hypoxia and among other things, Myelin Basic Protein (MBP).

suggesting a rescue of MBP expression defects by clemastine during chronic hypoxia
Daily treatment with oral clemastine during hypoxia leads to significant (3-fold) increases in MBP in the cerebellar foliae compared to untreated hypoxic littermates
We found that oral administration of clemastine in murine neonatal hypoxia leads to significant increases in the numbers of differentiating OPCs expressing the markers proteolipid protein (Plp) and myelin associated glycoprotein (Mag) mRNA in corpus callosum and striatum compared to untreated hypoxic littermates

Clemastine promotes myelin protein expression in neonatal hypoxia.(A) MBP protein expression in the (A) forebrain, (C) striatum white matter of postnatal Day 10 (P10) normoxic mice (‘Normoxia’), versus those exposed to neonatal hypoxia (‘Hypoxia’), versus hypoxic littermates treated with clemastine (‘Hypoxia + Clemastine’) 

Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest. 


The days of cheap clemastine in North America are probably numbered.

Friday, 17 November 2017

Beetroot - Cold Hands, Leukoaraiosis, Psychosis and Anxiety in Schizophrenia

Karimnagar, India, where Schizophrenic Rats respond well to Beetroot Juice

If you are not old enough to be interested in dementia, skip through those parts of this post and read about schizophrenic mice and beetroot juice.
There have been earlier posts regarding using nitric oxide (NO) to improve circulation and derive a cognitive benefit.
Many sportsmen have followed up on the research studies that show exercise endurance is improved after taking beet root juice. Since it is not a banned substance they are free to benefit from it.
We know that beet root does not only reduces blood pressure but it actually can increases perfusion, or blood flow, to the brain. Reduced blood flow to the brain is a feature of some dementia. Studies have used MRI to show that circulation is increased. A follow up study has recently been published which shows that beet root juice combined with exercise produced MRI results that resemble those of much younger adults.
In a previous post we saw that cocoa flavanols improved memory in older people and in effect brought them back to where they used to be 20 years previously. With cocoa the mechanism is not fully understood by is believed to “activate the nitric oxide system” in the brain. Cocoa does not produce nitric oxide in the way beet root does. Foods like beetroot and spinach contain large amounts of nitrates and they cause a measurable increase in circulating nitrites in the blood. The nitrites can later on become nitric oxide.
There is a lot of research into cocoa flavanols, mainly in relation to its benefit for those heart disease and more recently dementia. It also has benefits for anyone with diabetes, because it increases insulin sensitivity, as some readers of this blog have confirmed.
Cocoa flavanols appear to indirectly increase eNOS which then leads to more Nitric Oxide (NO). In addition there are antioxidant effects. eNOS reacts with L-arginine to produce NO.
But there is another way to make Nitic Oxide (NO), via nitrite that is circulating in your blood.  To increase nitrite you just eat nitrates, green leafy vegetables and beetroot.
It appears that eNOS does affect nitrite levels, so perhaps more eNOS means more NO is produced and then nitrite stays as nitrite and so the level of nitrite increases. Everything is inter-related.

Interestingly, statin drugs increase circulating nitrite levels just like beetroot.
NO bioavailability is determined by the balance between NO biosynthesis and its degradation by reactions with hemoglobin and reactive oxygen species (ROS).

So in people with oxidative stress there will be less NO. 

Nitric oxide (NO) is a potent signaling molecule that influences an array of physiological responses. It was traditionally assumed that NO was derived exclusively via the nitric oxide synthase (NOS) family of enzymes. This complex reaction requires a five electron oxidation of L-arginine and is contingent on the presence of numerous essential substrates (including O2) and co-factors. Recently an additional, O2-independent, NO generating pathway has been identified, where nitrite (NO2 ) can undergo a simple one electron reduction to yield NO. NO2 is produced endogenously from the oxidation of NO and also from the reduction of dietary nitrate (NO3 ) by facultative bacteria residing on the tongue. Recent data show that dietary NO3 supplementation, which increases the circulating plasma [NO2 ], reduces the O2 cost of submaximal exercise in healthy humans. This finding is striking given that efficiency during moderate-intensity exercise has been considered to be immutable. Therefore, dietary NO3 supplementation may represent a practical and cost-effective method to improve exercise efficiency and exercise tolerance in humans. Given that a NO3 -rich diet may have numerous cardiovascular and other health benefits, dietary NO3 intake may have important implications for human lifelong health and performance.
Cold hands
People with poor circulation tend to have cold hands and feet. From the comments in this blog it appears that many people with autism have cold hands/feet.
Do the many Nitric Oxide producing therapies used by sportsmen “warm up” cold hands?
Well we do actually now have some data on this subject. 

At least in the case of beetroot the answer is no.

L-arginine, L-citrulline, eNOS and NO    
It does appear that more eNOS can be beneficial. More eNOS means more NO as long as there is enough L-arginine. If you want to make more L-arginine, the most effective way is to eat L-citrulline, which is abundant in water melon.
It looks like some people lack arginine while others lack eNOS.  The males in clinical trials of citrulline and water melon, as a Viagra alternative, must lack L-arginine.
I think in autism the problem is lack of eNOS.
I thought L-citrulline might increase the positive effect of Agmatine that is very evident in Monty, aged 14 with ASD, but it has no additional effect.
Maybe some people do lack eNOS and l-arginine.
You do not need eNOS to make nitric oxide from the nitrites produced by beetroot juice.

We previously saw that the OTC supplement Agmatine increases eNOS, but it also actually affects BDNF.

Taken together, the findings of this study show that long-term agmatine administration increases the BDNF levels in both the hippocampus and amygdala, and also peripherally the NO synthesis and/or bioavailability, and corrects the age-related endothelial dysfunction, and hence may help in recovering vascular aging and vascular dementia.

Leukoaraiosis is a new word to this blog, it is very relevant to dementia, but it would likely only be relevant to autism if there has been hypoxia (lack of oxygen). Two readers of this blog do report hypoxia.
There is a lot of information in this blog about treating dementia and so for the sake of completeness I will elaborate further.
It appears that most people with Mild Cognitive Impairment (MCI) or dementia have lsome eukoaraiosis.
Leukoaraiosis also referred as ischemic demyelination or age-related white matter disease, is a radiological term given to white spots that appear on your MRI scan.

It is commonly observed in elderly people, and it is often a finding related to vascular dementia.  Histology from these lesions show atrophy of axons and decreased myelin. It is thought that localized hypoxia is what caused the damage.

On both CT and MRI, leukoaraiosis is characterized by bilateral patchy or confluent white matter changes.
So if your “autism” resulted from hypoxia, you might expect to see white spots on your MRI scan.
What is interesting is that leukoaraiosis may contribute to ongoing mild hypoxia.
It always seemed odd that people might benefit from HBOT (hyperbaric oxygen) years after they suffered acute hypoxia; but if the acute hypoxia left leukoaraiosis, perhaps this then reduces ongoing blood flow and thus leaves mild localized hypoxia, which does respond to treatment.
When blood flow is interrupted to part of the brain your doctor would call that a stroke.  A mini-stroke occurs when that blood flow is only temporarily interrupted.  These so-called transient ischemic attacks (TIA) are a warning sign of what may come shortly afterwards.
It appears in many people mini-strokes occur but remain unreported.
As a result of mini-strokes and/or leukoaraiosis perfusion in older people is not as good as in younger people and so cognition and memory suffer.
This can be partially addressed by making your blood more “slippery” using low dose aspirin, but the risk is that over the years blood vessels have narrowed and become brittle.  You then risk micro bleeds where the blood vessel cracks and the “slippery” blood can leak out.  This does happen in the brain
Cerebral microbleeds are not rare and are seen as another cause of cognitive impairment.

The conclusion for adults is that prevention is much better than cure. A diet rich in nitrates (spinach beetroot etc) and flavanols (cocoa etc) plenty of exercise and avoiding half a century of high cholesterol looks a wise choice. 

Emerging evidence suggests that silent strokes or lacunar infarctions, leukoaraiosis, and vascular diseases may be associated with cognitive impairment including dementia. We assessed the occurrence of these risk factors among various spectrum of cognitive dysfunction. A retrospective review of patients evaluated in Guam with the diagnosis of Memory Loss, Mild Cognitive Impairment (MCI) and Dementia from August 2006 to December 2014 was conducted. The history of stroke and co-morbid vascular diseases was identified. The neuro-imaging studies were reviewed to determine the presence of silent strokes and leukoaraiosis in patients without history of a clinical stroke. There were 585 patients included in the analysis. One hundred forty two patients having a diagnosis of memory loss, 95 have MCI and 348 have dementia. A history of stroke was present in 29% of patients with Memory Loss, 20% of patients with MCI and 30% of patients with dementia. Silent strokes without a history of clinical stroke were present in 10% of patients with memory loss and MCI, and 15% of patients with dementia. The presence of Leukoaraiosis was present in 50% of patients with memory loss, 56% of patients with MCI, and 60% of patients with dementia. Occurrences of vascular diseases were higher in patients with dementia than patients with Memory Loss and MCI. In conclusion, silent strokes, leukoaraiosis and vascular diseases are found to be more prevalent in patients with Dementia than those with Memory Loss and MCI.  

Oxygen deprived areas of the brain can change the way the brain functions in older adults. These areas of the brain were thought to be just a normal part of aging and could lead to other diseases such as Alzheimer's or stroke.
Leukoaraiosis is described as a condition where brain scans (CT or MRI) show bright white dots. These areas of the brain are deprived of oxygen and were considered to be a normal part of aging process.
"There has been a lot of controversy over these commonly identified abnormalities on MRI scans and their clinical impact. In the past leukoaraiosis has been considered a benign part of the aging process, like gray hair and wrinkles," said Kirk M. Welker, M.D., assistant professor of radiology in the College of Medicine at Mayo Clinic in Rochester, Minn., in a press release.
The condition is common in people who are above the age of 60. Recently, leukoaraiosis has been linked to diseases like Alzheimer's, hypertension and stroke.
"We know that aging is a risk factor for leukoaraiosis, and we suspect that high blood pressure may also play a role," Dr. Welker said.
Researchers from the Mayo Clinic obtained brain scans from 18 participants over the age of 60. The brain scans of these participants were matched against those obtained from a control group. Researchers found that these participants had lesions in the brain that were 25 millimeters long while some lesions in the brains of control group participants were about five millimeters long.
The participants were given tests based on words and visual patterns. All the participants were connected to brain scanners during the tests.
The participants of control group and study group completed the task with similar speed. However, researchers found that the brains of people who had moderate leukoaraiosis worked differently than people who had mild lesions.
They found that areas of brains that performed word-association tasks weren't activated during the test but areas that process visual patterns were highly activated.
"Different systems of the brain respond differently to disease. White matter damage affects connections within the brain's language network, which leads to an overall reduction in network activity," Dr. Welker said.
Welker said that diagnosing leukoaraiosis is important in people who are above 60, especially those who have to undergo brain surgery and those who are part of scientific research study.
Previous research shows that the probability of stroke increases with increase in leukoaraiosis spread.
"Our results add to a growing body of evidence that this is a disease we need to pay attention to Leukoaraiosis is not a benign manifestation of aging but an important pathologic condition that alters brain function," Welker said.  

Finally, now you know all about leukoaraiosis, back to beet root juice.

Exercise has positive neuroplastic effects on the aging brain. It has also been shown that ingestion of beet root juice (BRJ) increases blood flow to the brain and enhances exercise performance. Here, we examined whether there are synergistic effects of BRJ and exercise on neuroplasticity in the aging brain.
Peak metabolic equivalent (MET) capacity and resting-state magnetic resonance imaging functional brain network organization are reported on 26 older (mean age = 65.4 years) participants randomly assigned to 6 weeks of exercise + BRJ or exercise + placebo.
Somatomotor community structure consistency was significantly enhanced in the exercise + BRJ group following the intervention (MBRJ = -2.27, SE = 0.145, MPlacebo = -2.89, SE = 0.156, p = .007). Differences in second-order connections between the somatomotor cortex and insular cortex were also significant; the exercise + BRJ group (M = 3.28, SE = 0.167) had a significantly lower number of connections than exercise + placebo (M = 3.91, SE = 0.18, p = .017) following the intervention. Evaluation of peak MET capacity revealed a trend for the exercise + BRJ group to have higher MET capacity following the intervention.
Older adults who exercised and consumed BRJ demonstrated greater consistency within the motor community and fewer secondary connections with the insular cortex compared with those who exercised without BRJ. The exercise + BRJ group had brain networks that more closely resembled those of younger adults, showing the potential enhanced neuroplasticity conferred by combining exercise and BRJ consumption.  
BRJ is clearly an encouraging nutritional supplement that may improve functional health in older adults, and the proposed primary mechanism of benefit of BRJ is the rise in plasma nitrite caused by the high levels of dietary nitrate in BRJ (32). Consumed nitrate, once absorbed from the intestine, is taken up from the plasma by salivary glands and concentrated in saliva; nitrate is subsequently reduced to nitrite by oral bacteria and ultimately absorbed into the circulatory system (32,33). Nitrite appears to be reduced to NO during hypoxia. NO is an antioxidant and a potent vasodilator (34,35), is a critical relaxation factor synthesized in endothelial cells (36,37), and is key to vascular compliance. For this study, we hypothesized that reductions in brain blood flow associated with hypertension and aging associated leukoaraiosis result in low-grade hypoxia (38) and that these reductions might be offset by the NO-mediated vasodilation in hypoxic regions due to the increased amount of circulating nitrite from the BRJ ingestion. Indeed, results from our lab have shown that 24 hours of a high nitrate diet supplemented with a single dose of BRJ leads to increased regional CBF in older adults (39). Coupled with exercise (a hypoxia-inducing activity), we propose that the biological mechanism underlying the neural plasticity shown in Figure 1 resulted from increased NO bioavailability after drinking BRJ

Supplementation with nitrate (NO3)-rich beetroot juice has been shown to improve exercise performance and cardiovascular (CV) responses, due to an increased nitric oxide (NO) availability. However, it is unclear whether these benefits are greater in older adults who have an age-related decrease in NO and higher risk of disease. This systematic review examines 12 randomised, crossover, control trials, investigating food-based NO3 supplementation in older adults and its potential benefits on physiological and cognitive performances, and CV, cerebrovascular and metabolic health. Four studies found improvements in physiological performance (time to exhaustion) following dietary NO3 supplementation in older adults. Benefits on cognitive performance were unclear. Six studies reported improvements in CV health (blood pressure and blood flow), while six found no improvement. One study showed improvements in cerebrovascular health and two found no improvement in metabolic health. The current literature indicates positive effects of dietary NO3 supplementation in older adults on physiological performance, with some evidence indicating benefits on cardiovascular and cerebrovascular health. Effects on cognitive performance were mixed and studies on metabolic health indicated no benefit. However, there has been limited research conducted on the effects of dietary NO3 supplementation in older adults, thus, further study, utilising a randomised, double-blind, control trial design, is warranted.
Beet Root and Schizophrenia
Having read about cocoa and beet root a long time ago, I did try both on myself. I think beet root has effects that go well beyond lowering blood pressure.
There are of course no trials of beet root in autism, but there is one in the next closest thing, schizophrenia. Unfortunately it was in rats, but nonetheless the findings are interesting.
In recent years, there has been much focus on the apparent heterogeneity of schizophrenic symptoms. By contrast, this article proposes a unifying account emphasizing basic abnormalities of consciousness that underlie and also antecede a disparate assortment of signs and symptoms. Schizophrenia, is fundamentally a self-disorder or ipseity disturbance is  characterized by complementary distortions of the act of awareness, hyper reflexivity and diminished self-affection. Anxiety impacts people in ways that they are unaware. In the presence of anxiety, attention is highly directed towards threatening information. Recently, anxiety was found to impact task switching performance when threatening stimuli were present. In the current study, we examined the Anxiolytic and antipsychotic activity of Beet Root Juice (BRJ) in rats. This study reveals that the BRJ has showed decreased effects of turning behaviour, weaving behaviour, head bobbing and falling behaviour. It also showed decreased effect of loco motor activity and increase in catalepsy scoring. Thus it shows anti psychotic and anti anxiety effects.

Ketamine-Induced Stereotypic Behaviour in Mice
Animals were divided into five groups and each group consisted of four animals. The control animals received normal diet and treated with Ketamine (50 mg/kg) for 15 consecutive days. The animals of standard groups received Olanzapine (5 mg/kg) after 30 min Ketamine was given, (50 mg/kg) for 15 consecutive days. The animals of test groups received different concentrations of BRJ (2 , 4, 8% w/w) through a specially prepared diet and after 30 min Ketamine was given (50 mg/kg) for 15 consecutive days. Each rat was individually placed into plastic cages (37 × 24 × 30 cm3) divided into quadrants by lines on the floor and allowed to acclimatize for at least 30 min before the testing began. Behavioural tests were performed between 10 a.m. and 4 p.m. The stereotypic behaviour was assessed by counting the number of turning, weaving, head-bobbing and ataxia. Turning was measured by counting turn around every 15 min over 60 min. Weaving and head-bobbing were measured by counting its neck wave right and left, and go up and down every 15 min over 60 min. Ataxia was assessed by counting the number of falls of each rat on the floor of the cage every 15 min over 60 min period

Beet root juice was as effective as Olanzapine, an antipsychotic medication used to treat schizophrenia and bipolar disorder. (Ketamine is what creates the stereotypy)

Beet root juice was more effective than Haloperidol, a typical antipsychotic medication used in the treatment of schizophrenia, tics in Tourette syndrome and  mania in bipolar disorder

Beet root was as effective as Diazepam (aka Valium), is a medication of the benzodiazepine family that typically produces a calming effect 

I found the above paper very surprising. It certainly supports my feeling about the effects of beet root juice being beyond just lowering blood pressure. It definitely has a calming effect on me, so it is not just in rats.

Beetroot Juice for Autism?
Why not try just try it?
It does taste better when it is 25% apple juice and 75% beetroot.
You can also use freeze dried beetroot powder, which can be put in capsules.
It is not clear the amount of powder you need.
>150 ml a day of juice gives the exercise endurance effect and the calming (Diazepam) effect.  I would guess 2 or 3 fresh beet root would be equivalent.
Freeze dried beet root powder appears to remove 90% of the weight. So 3g of powder equals about 30g of beetroot.
Some people use a teaspoon of beetroot powder to control blood pressure. 
I expect there are studies on beetroot powder and blood pressure.
I concluded in Monty, aged 14 with ASD, that while Agmatine has a significant effect from the first day citrulline has no noticeable effect whatsoever (so no lack of L-arginine).  Having just read about the rats from Karimnagar, India in the above study I started offering Monty some of my beetroot juice. I have filled some large gelatin capsules with freeze dried beetroot, but it is not clear how much you would need.  Better to stick with the juice and see if it does anything.
Beet root is rich in betaine, which is also good for you.
I think Agmatine increases eNOS and also NO, by increasing dietary nitrate we make more nitrite which is available to make more NO as it gets depleted by oxidative stress (Reactive Oxygen Species). It looks like some people with autism have no shortage of L-arginine and so there is no effect from arginine or citrulline supplementation.
I think there is a rationale to consider Agmatine and Beetroot juice. We do have the surprising results from the schizophrenic rats, which do suggest there can be a benefit. 
I have to say that after a year of drinking 150ml of beetroot juice a day, I am a convert. You do get used to the taste. 
Beetroot, cinnamon and cocoa flavanols are quite potent potential non-drug therapies for dementia and not forgetting where you left your car keys.

Thursday, 19 October 2017

Unstable Blood Flow in Autistic Brains?

Today’s post is complicated, but may be of interest to those people interested in Nitric Oxide therapies (Agmatine, Cocoa Flavanols, Beetroot, Taurine, Citrulline etc) and those who think they are treating earlier hypoxia/ischemia.
As usual, I am making simplifications, but the science behind the general ideas already exists. When it comes to the details regarding VEGF and autism, there are big gaps in the science. 
We have already seen that something as simple as improving blood flow appears to be therapeutic in some people with autism. Perhaps there should even be a post called “cold feet and autism”. 
One reader of this blog, Seth, has commented before that he sees autism as essentially vascular in nature.  Today’s research suggests it does indeed include microvascular abnormalities.
Rather than simply reduced blood flow, the problem, in at least some autism, appears to be unstable blood flow, which is much more complex.
I do take a leap in logic to suggest that this is likely linked to the known abnormalities in Vascular Endothelial Growth Factor (VEGF) and in VEGF receptor 1 (VEGFR-1).  It also appears that the VEGF anomalies that lead to angiogenesis may be part of the reason for the increased prevalence of chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis.
Ideally you might want to normalize VEGF, even later in life. The use of anti-angiogenic drugs has been suggested.  Angiogenesis inhibitors were once seen as potential wonder drugs to treat cancer.
It does seem that just simply targeting vascular resistance is helpful for some people with autism.   
VEGF is regulated by many things, some are highly complex and are usually studied with regard to cancer, like Wnt signaling and Ras. Recall that both Wnt and Ras are relevant to autism. One simple thing that influences VEGF is nitric oxide (NO), but it is not a simple relationship. As highlighted by our reader Tyler, intermittent fasting (IF) can also be used to increase VEGF. Research suggests that intermittent fasting (IF) is actually a simple but potent tool to both prevent and treat metabolic disorders, including but not limited to type 2 diabetes.

In the case of autism, where both VEGF and NO are likely to be low, it does seem quite likely that by increasing the production of NO you will increase the expression of VEGF. So the amino acid L-citrulline is likely to increase VEGF.
In the rat study below, L-citrulline increased eNOS and VEGF; we presume NO also increased. 

Blood Flow in Autistic Brains
Now we get to the autism-specific research.

A team of scientists has found evidence that people with autism have unstable vessels in the brain which prevents the proper delivery of blood flow, according to research published in the Journal of Autism and Developmental Disorders
“In a typical brain, blood vessels are stable, thereby ensuring a stable distribution of blood,” said Patricia Whitaker-Azmitia, PhD, professor in the Department of Psychology and director of the Graduate Program in Integrative Neurosciences at Stony Brook University, N.Y.,  in a statement. “Whereas in the autism brain, the cellular structure of blood vessels continually fluctuates, which results in circulation that is fluctuating and, ultimately, neurologically limiting.”

Sustained angiogenesis may contribute to prolonged neuroplasticity in the ASD brain. We propose the sustained splitting angiogenesis is a necessary component to maintain the heightened neuronal activity reported in ASD patients. Many biological and functional indicators are increased in ASD including cerebral metabolic rate, regional synchronous electrical activity sensitivity to sound; cortical activity in deactivation centers at rest, low-level visuospatial processing, visual-tactile interactions; attention to low-level perceptual information and over-connected, redundant cortical networks. It can be suggested that sustained rearrangement of microvasculature permits excessive shorter and local connections to be maintained and prevents the growth of longer and more complex brain connections required for language and social interactions. Use of anti-angiogenic drugs may provide a novel treatment strategy for reducing neuronal activity in ASD patients by inhibiting vascular plasticity.

Brain tissue from children (left) and adults (right) with autism (top) but not controls (bottom) shows dividing cells lining blood vessels.

Angiogenesis and Lymphangiogenesis
It looks like, at least in today’s subgroup of autism, we want less angiogenesis but more lymphangiogenesis.  The ideal way to do this is via VEGF/VEGFRs.
Here it may be helpful to explain the meaning of some new terminology.

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer.”
Lymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels in a method believed to be similar to angiogenesis (blood vessel development).

Lymphangiogenesis plays an important physiological role in homeostasis, metabolism and immunity. Impaired or excessive lymphatic vessel formation has been implicated in a number of pathological conditions including neoplasm metastasis, oedema, rheumatoid arthritis, psoriasis, lymphangiomatosis and impaired wound healing.”

Lymphatic system and the Brain 
As highlighted recently by our reader Tanya, a pretty basic gap in science’s understanding of how the brain works has just been addressed. It is all about where do the waste products produced in the brain go to.
Scientists have found evidence that the brain is connected to body’s central lymphatic system.
This then begs the question of what happens when this system does not work well. Is this a feature of some neurological disease? If that were the case, it would likely be associated with reduced lymphangiogenesis.

Running through your body is a network of channels and junctions called the lymphatic system, which siphons off waste and fluids like a biological sewer.
It was long thought the brain was excluded from this web of anatomical plumbing. After being spotted in mice brains two years ago, researchers have now confirmed the presence of lymphatic vessels in human brains, fueling speculation over the kinds of diseases they might be responsible for.

VEGF and VEGF receptors 
There are four types of VEGF and they act through three types of receptors. Confusingly, the receptors have been given multiple names.

In severe autism there is reduced VEGF, but we do not know which type(s) but there is increased expression of the receptor  VEGFR-1 also known as Flt-1. VEGFR-2 expression is normal, this is the best understood receptor.

This receptor VEGFR-1 is activated by VEGF-A and VEGF-B.  


To study vascular endothelial growth factor (VEGF) and its soluble receptors sVEGFR-1 and -2 in autism.

Design and methods:

We measured serum levels of angiogenic molecules in 22 patients with severe autism and 28 controls.


Patients and controls had similar sVEGFR-2 levels, but VEGF levels were lower and sVEGFR-1 higher in patients with autism.


The imbalance between VEGF and its receptor sVEGFR-1 may be involved in the pathophysiology of autism.

Hypoxia related autism 
It is well known that hypoxia-ischemia insults early in life can cause cognitive dysfunction and likely autism.  In the very recent paper below, it is suggested that altered VEGF signaling is the mechanism that causes the damage to the brain. 

Neurovascular dysfunction and the role of vascular endothelial growth factor (VEGF) have been explored in neurodevelopmental disorders including schizophrenia, bipolar disorder, major depressive and mood disorders, and autism. These disorders are correlated with hypoxia-ischemia insults during early life and are strongly associated with cognitive dysfunction. This review focuses on the hypoxia-regulated protein, VEGF, to discuss its crucial roles in brain development and function. These data implicate that alterations to VEGF signaling during early life can impair neural development, underlying the severe cognitive deficits observed in neurodevelopmental disorders.
Recent Findings
VEGF has been linked to neurological processes that influence learning and memory. VEGF is advancing towards being a novel biomarker and possible therapeutic for neurological disorders. Prenatal environmental enrichment positively impacted neurotrophic factors, brain structure, and memory in rodent models.
Understanding the molecular mechanisms of VEGF in neurodevelopment will create intervention strategies for at-risk children born to adverse early-life events. By proactively working with those in a pliable neurodevelopmental state, we hope to ameliorate cognitive deficits to increase their chance to develop into high-functioning adults with disabilities. 

Hypoxia-Induced Angiogenesis - Good and Evil

Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function.
VEGF, considered a master regulator of angiogenesis in its own right, causes endothelial cells to detach from the parent vessel and migrate into the neighboring stroma. Hypoxia is the principal regulator of VEGF expression, as it is a direct transcriptional target of both HIF-1α and HIF-2α.

Allergy and inflammation resulting from angiogenesis 
It appears that in some people another consequence of too much angiogenesis is allergy and other inflammatory disease; these are of course often comorbid with autism.  This suggests anti-angiogenic and pro-lymphangiogenic therapies.

Angiogenesis and lymphangiogenesis, the growth of new vessels from preexisting ones, have received increasing interest due to their role in tumor growth and metastatic spread. However, vascular remodeling, associated with vascular hyperpermeability, is also a key feature of many chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis. The major drivers of angiogenesis and lymphangiogenesis are vascular endothelial growth factor- (VEGF-)A and VEGF-C, activating specific VEGF receptors on the lymphatic and blood vascular endothelium. Recent experimental studies found potent anti-inflammatory responses after targeted inhibition of activated blood vessels in models of chronic inflammatory diseases. Importantly, our recent results indicate that specific activation of lymphatic vessels reduces both acute and chronic skin inflammation. Thus, antiangiogenic and prolymphangiogenic therapies might represent a new approach to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.

Figure 1: VEGF-binding properties and distinct VEGF receptor expression on lymphatic and blood vascular endothelium. VEGFs bind to the three VEGF receptor tyrosine kinases, leading to the formation of VEGFR dimers. Blood vascular endothelial cells express VEGFR-1 and VEGFR-2, whereas lymphatic endothelial cells express VEGFR-2 and VEGFR-3. VEGF-A—which binds both VEGFR-1 and VEGFR-2—can directly induce blood and lymphatic vascular remodeling. VEGF-C and -D bind VEGFR-3 and, after proteolytic processing, also VEGFR-2, thus inducing angiogenesis and lymphangiogenesis.

There is clear evidence that in humans, vascular remodeling occurs in many chronic inflammatory disorders. Even though different anti-inflammatory drugs are on the market, there is no specific therapy that interferes with the pathological vascular changes that occur during inflammation. Angiogenesis and lymphangiogenesis are tightly linked to chronic inflammation, and targeting the blood vessels and lymphatic vessels has been shown to be an effective strategy in different experimental mouse models of chronic inflammation. One has to keep in mind, however, that in most conditions the vascular activation likely represents a downstream event that maintains the inflammatory process, but not the pathogenetic cause of the respective disease, which often has remained unknown. Nonetheless, antiangiogenic and prolymphangiogenic therapies might represent new approaches to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.

I did start this post by saying this subject is complicated.
From the previous post on nitric oxide, it looked like L-citrulline, L-norvaline, Agmatine and other NO increasing substances could be therapeutic. Cold hands and feet seem to be very common in autism.
It seems likely that the NO increasing therapies will likely also increase VEGF, which I think is a good thing.
From today’s post we see that rather than just a single VEGF we have five broad types (A,B,C, D and PIGF), but even just VEGF-A has various different forms. We do not have detailed research on autism and specific subtypes of VEGF. 
We have the four different VEGF receptors and we know VEGFR-1 is over expressed. We do not have a clever way to counter this. More VEGFR-3 expression would be helpful and that is again a case of changing the balance between inflammatory cytokines, which as we know is usually disturbed in autism.
The inflammatory cytokine IL-6 induces VEGF-C production which leads to both angiogenesis and lymphangiogenesis; this is why people with cancer and high IL-6 may have a poor prognosis.
Regarding VEGF and autism we clearly lack 95% of the science. Strange things are afoot and we are just guessing.
For the time being, I see increasing vascular permeability via eNOS as therapeutic, even though today’s post suggests that antiangiogenic therapies could be helpful, which may seem contradictory.
The kind of drugs that would reduce the activity of VEGFR-1/Flt-1 would be very expensive cancer drugs.  Hypoxia also downregulates VEGFR-1/Flt-1.
Inflammatory cytokines regulate VEGFR-3/Flt-4 and hence control of lymphangiogenesis.  Interferon gamma (IFNγ) upregulates VEGFR-3/Flt-4, while Interleukin 1 beta (IL1β) down regulates it. 
So more IFNγ and less IL1β might help.
Although expensive, interferon gamma (IFNγ) has been shown to be effective in treating severe atopic dermatitis. This would make sense since it induces lymphangiogenesis and the research suggests this should improve inflammatory disease.


We conclude that rIFN-gamma appears to be a safe long-term therapy for patients with severe atopic dermatitis.

So perhaps interferon-gamma (IFNγ) for some autism? Quite possibly, just look for the ones with asthma, atopic dermatitis, psoriasis or juvenile arthritis.