Longitude, Latitude & Epilepsy in Autism

It is not always easy to decide which subjects to study, never mind if you have autism.

For Monty, aged 12 with autism, it has been me choosing what he studies.  At the beginning it was rather overwhelming for his 1:1 assistant, because there was so much to learn and never enough time.  It takes years to learn very simple things that typical kids just pick up naturally.

One big change after three and half years of Polypill use, is that Monty follows the standard academic curriculum, albeit for kids two years his junior.

An excellent but not very user friendly curriculum/skill list is in a book called ABLLS (assessment of basic language and learning skills).  It is both a curriculum and an assessment tool.  It covers all the very basic skills that kids need as a foundation for future learning.

We were working from this list of simple skills for four years, until the age of eight.  These are skills most kids effortlessly pick up in the first three or four years of life.

After you have mastered those simple skills what do you teach next to someone with classic autism?

I did my research and concluded the generally accepted answer is “not much”.

One phrase I still recall was a mother writing “our kids don’t need to learn longitude and latitude”, because this is going to go way over their heads.

It seems that for kids entirely non-verbal at three, about 10% have some maturational dysfunction that self-corrects by six, leaving just minor tics or perhaps mild "quirky" autism. Most of the remaining 90% end up "graduating" high school with an academic level of a four to seven year old.  A small number do better.  

A few years after ABLLS and Monty has mastered X,Y coordinates, even using negative numbers and identifying objects using Northwest, Southeast etc.

Regular readers will be aware that Monty’s recent academic development did not happen spontaneously, nor through ABA, it came from pharmacotherapy (drugs) and is reversible (hopefully not entirely).

Burden of proof

In spite of all this change it would be hard to prove what has caused it. Fortunately I do not need to.

Monty is still autistic, just less so and is now educable. That is a really big deal to me, but not to others. 

If you could convert 100% of kids with autism into outgoing, talkative, social, intelligent, typical kids then people would take note.  No therapy will ever deliver this. Just to confuse the issue, 10% will indeed "recover" without any intervention at all, which then is used to justify all kinds of interventions that those people used.

Have I measured Monty’s IQ?  No I have not.  A lady from California asked me why not, because over there they have excellent autism services, even assisted employment and sheltered housing but it is rationed based on things including IQ. 

One doctor reader of this blog suggested that some of the drug interventions in this blog will also reduce the development of seizures and therefore reduce the rate of premature death in autism; “surely we should tell people about this”.  I had a sense of déjà vu.

It is clear that in treating the excitatory/inhibitory imbalance that underlies much autism and also treating other channelopathies, you should also be avoiding some of the neuronal hyper-excitability that is epilepsy.

So treating autism should reduce death from seizures that reduce life expectancy in severe autism to just 40 years old.

This is all true and a year or so back I did suggest this to the Bumetanide researchers.  There was little interest and some skepticism. 

In fact there is a great deal of epilepsy research and some does indeed overlap with autism research.  One key area is Cation Chloride Cotransporters (CCCs), where the same type of immature neurons found in autism are found in epilepsy. Another is elevated BDNF (brain-derived neurotropic factor); in epilepsy, seizures trigger an increase in BDNF which then reduces expression of KCC2 which then shifts neurons further towards immature (high intra-cellular chloride) worsening the excitatory/inhibitory imbalance and making the next seizure more likely.  A clever idea we can borrow from the under-utilized epilepsy research is to consider blocking BDNF, or trkB, as a means of increasing KCC2 expression.  This could be a useful adjunct therapy to bumetanide, which blocks NKCC1. We want less NKCC1 but more KCC2, to give lower levels of chloride inside the cells and then neurons can fire when they are supposed to.

It takes decades for research findings, like those in the above paragraph, to be translated across into therapies.

If you, or particularly a researcher, make a statement that is controversial and not backed by a big stack of evidence (based on human trials, not mouse trials) nobody is going to believe you.  Worse still, the next time you make a claim, they will be even less likely to believe you.

So better under-promise but over deliver.  Start finally treating some autism and then watch in the next thirty years that epilepsy incidence falls and along with it SUDEP (Sudden Unexpected Death in Epilepsy).  Then you can say “I told you so, it was those Cation Chloride Cotransporter after all ”.

In spite of all the “evidence” that some autism is treatable, cognitive dysfunction is reversible, the world has not taken any notice.  Where is the undisputed concrete proof?  I just have to think “longitude and latitude”, that’s my proof.

So in reality while avoiding epilepsy should be a big deal for the parents, it is not for anyone else.  The current wisdom is keep your fingers crossed and hope that you are not in the one third that will develop epilepsy around puberty.  In some people this triggers an epigenetic change, opening the way to many future seizures.  For those who are interested:-

          Epigenetics and Epilepsy

If you follow 100 kids with autism on bumetanide for 10 years and found 5 developed seizures that would not be regarded as proof.

Based on my reading of the literature, you would expect 30+% of people with classic autism to develop epilepsy.  So if they had just 5 cases, I would see that as vindication, but it would not be seen as conclusive proof by others, just another paper to file and forget.

So the idea of prophylactic drug treatment to avoid the onset of epilepsy in autism is unlikely to catch on and is easy to rubbish.

Just like prophylactic use of drugs to avoid dementia, avoid type 2 diabetes or avoid the nasty side effects of type 1 diabetes, they will not enter the mainstream.

Conclusion

Setting low standards and targets will guarantee poor outcomes.  Aim to learn longitude and latitude, but it might be easier with a daily dose of bumetanide.

Some epilepsy is avoidable, some may not be, but if treating autism can also reduce the chance of epilepsy and SUDEP do you really need to wait for absolute evidence?

It is currently a matter of geography and google competence who is going to access effective pharmacotherapy.  For a change it is the poorer countries who have the advantage, since they have less rigid control over access to prescription medication.

I was just reading that the excellent New England Center for Children (NECC) charges up to $300,000 a year to educate kids with autism.  It is a great school and we employed a former teacher from there a few years ago, to help with our home program.  With something like 0.3% of all kids having serious autism, there needs to be a less expensive solution available to all.  

Spending $300,000 at NECC will almost definitely have a positive impact on one severely autistic child for one year.  Alternatively, for the same money, you could treat 480 kids with strict definition autism with my Polypill for one year.  It looks like around a half would respond very well.  Ideally you would spend $300,620 and have both the NECC and the Polypill; this is pretty much what was my target, but without leaving home.

 

Autophagy, Mitophagy, Calpains and mTOR in Autism, but also in aging, cancer, diabetes, Alzheimer's, Parkinson's, and Huntington's etc.

 Source:  http://www.tanpaku.org/autophagy/

I am writing a science heavy post all about a protein called mTOR.  It is one of those "cancer proteins" that are now heavily researched, very complicated, but clearly very connected to autism.

In today’s lead-in post, that was not supposed to get complicated, I will introduce new terms, Autophagy, Mitophagy and Calpains. 

There are some very interesting implications from the research, not least that you can reduce mTOR levels just by eating (a lot) less.  Indeed, this “starvation” diet has now been shown by the University of Newcastle to be able to reverse the onset of type 2 diabetes.  It also may suggest another reason for those Somali Autism clusters in the US and Sweden, where refugees from Somalia have been settled.  Just as a starvation diet reduces mTOR, excessive eating increases mTOR.  Via several mechanisms we will see that autism associates with high levels of mTOR.  While the hygiene hypotheses can be used to explain these autism “hotspots” among Somali refugees, a completely different reason might be the switch from relative starvation to an overabundant diet; this would trigger an increase in mTOR and therefore the increase in autism (and later diabetes and cancer in the wider group).

In today’s post we will find out about Autophagy/Mitophagy and see how they are relevant to autism.

We will see how they are generally controlled by mTOR.  PINK1, which we encountered in a previous post will reappear, as will Verapamil, that L-type calcium channel blocker that seems to affect so many things.

Not only does verapamil appear protective towards developing type 2 diabetes, but also now Huntingdon’s Disease.

Autophagy

Autophagy is a very complex process.

Here is a relatively plain English explanation:

The word autophagy is derived from Greek words “auto” meaning self and “phagy” meaning eating. Autophagy is a normal physiological process in the body that deals with destruction of cells in the body.

It maintains homeostasis or normal functioning by protein degradation and turnover of the destroyed cell organelles for new cell formation.

During cellular stress the process of Autophagy is upscaled and increased. Cellular stress is caused when there is deprivation of nutrients and/or growth factors.

Thus Autophagy may provide an alternate source of intracellular building blocks and substrates that may generate energy to enable continuous cell survival.

Autophagy and cell death

Autophagy also kills the cells under certain conditions. These are form of programmed cell death (PCD) and are called autophagic cell death. Programmed cell death is commonly termed apoptosis.

Autophagy is termed a nonapoptotic programmed cell death with different pathways and mediators from apoptosis.

Autophagy mainly maintains a balance between manufacture of cellular components and break down of damaged or unnecessary organelles and other cellular constituents.

There are some major degradative pathways that include proteasome that involves breaking down of most short-lived proteins.

Autophagy and stress

Autophagy enables cells to survive stress from the external environment like nutrient deprivation and also allows them to withstand internal stresses like accumulation of damaged organelles and pathogen or infective organism invasion.

Autophagy is seen in all eukaryotic systems including fungi, plants, slime mold, nematodes, fruit flies and insects, rodents (laboratory mice and rats), humans.

Types of autophagy

There are several types of Autophagy. These are:-

·         microautophagy – in this process the cytosolic components are directly taken up by the lysosome itself through the lysosomal membrane.

·         macroautophagy – this involves delivery of cytoplasmic cargo to the lysosome through the intermediary of a double membrane-bound vesicle. This is called an autophagosome that fuses with the lysosome to form an autolysosome.

·         Chaperone-mediated autophagy – in this process the targeted proteins are translocated across the lysosomal membrane in a complex with chaperone proteins (such as Hsc-70).  

·         micro- and macropexophagy

·         piecemeal microautophagy of the nucleus

·         cytoplasm-to-vacuole targeting (Cvt) pathway

Autophagy & Autism

Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits

Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2 ± ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2 ± mice, but not in Atg7(CKO) neuronal autophagy-deficient mice or Tsc2 ± :Atg7(CKO) double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR.

Verapamil, Autophagy and Calpains

Here we need to introduce another new term, the calpain.

Hyper activation of calpains is a feature of Alzheimer’s and Huntingdon’s disease.  This does lead to altered calcium homeostasis.

Nobody has really studied calpains and autism.  There is research into calpains and TBI (traumatic brain injury).

Since we know there is aberrant calcium channel activity in autism and even excessive physical calcium present in autistic brains, it seems possible that hyper activation of calpains may be occurring in autism.

We also know that calpains play a role in degrading PTEN, which then affects BDNF, in turn affecting mTOR activation.  So everything is highly interrelated.

Calpain may be released in the brain for up to a month after a head injury, and may be responsible for a shrinkage of the brain sometimes found after such injuries.

However, calpain may also be involved in a "resculpting" process that helps repair damage after injury.

Moreover, the hyperactivation of calpains is implicated in a number of pathologies associated with altered calcium homeostasis such as Alzheimer's disease

  

Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis

From: Biomarkers of Brain Injury

 Source:-  Stanford Huntingdon Disease (HD) Project

So if it was the case that in autism, as in HD, that there is excessive calpain activity, then it would be possible to increase autophagy simply by reducing the flow of calcium into the cells. 

So this might be yet another reason why Verapamil may be a good therapeutic choice for some people with autism.

Mitophagy & PINK1

Mitophagy is a necessary ongoing “spring cleaning” of damaged bits of mitochondria.

It appears that in some autism, this process goes awry and damaged mitochondria accumulate.

We saw in early posts that in brain samples from younger people with autism, abnormal mitochondria are typically found.

Mitochondrial abnormalities in temporal lobe of autistic brain

Children with autism have mitochondrial dysfunction, study finds

I should point out that there are various types of mitochondrial disease and dysfunction.

It appears that some people’s autism is solely the result of mitochondrial disease, but a much broader group have some mitochondrial dysfunction.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. This process was first mentioned by J.J. Lemasters in 2005, although lysosomes in the liver that contained mitochondrial fragments had been seen as early as 1962, “As part of almost every lysosome in these glucagon-treated cells it is possible to recognize a mitochondrion or a remnant of one. It was also mentioned in 1977 by scientists studying metamorphosis in silkworms, “...mitochondria develop functional alterations which would activate autophagy."  Mitophagy is key in keeping the cell healthy. It promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria which can lead to cellular degeneration. It is mediated by Atg32 (in yeast) and NIP3-like protein X (NIX). Mitophagy is regulated by PINK1 and parkin protein. The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.

Autophagy and mitophagy in cellular damage control

Mitochondrial dysfunction due to aberrant mTOR-regulated mitophagy in autism

This Mentored Research Scientist Development Award (K01) is designed to characterize the molecular mechanism underlying mitochondrial dysfunction in autism, with the eventual goal of identifying therapeutic interventions for mitochondrial defects. The applicant (Dr. Guomei Tang) is an Associate Research Scientist at Columbia University Medical Center (CUMC), where internationally renowned basic neuroscience research in psychiatry has been ongoing for many years. CUMC provides a rich environment that supports and encourages Dr. Tang's development and this K01 award will be instrumental for her successful transition to an independent research investigator. Dr. Tang has recruited an outstanding team of mentors, co-mentors, consultants and collaborators with extensive experience in mitochondrial biology and diseases, neuropathology, psychiatry neuropathology, neuroscience, molecular and cell biology, and mTOR-autophagy signaling. These experts will provide her with critical guidance and advice, and enhance her technical and scientific skills for the proposed research. The career development activities include tutorials, directed readings, course work, workshops for mitochondrial biology, skills in collaborating with clinicians and senior scientists, grant writing and presentations, and responsible conduct of research. Dr. Tang's long term research goal is to elucidate the molecular and cellular mechanisms underlying synaptic pathology in autism, and to provide insights into the pathogenesis and potential treatment for autism. To accomplish this, Dr. Tang will use a multidisciplinary approach combining biochemical, histological and imaging techniques to examine mitochondrial autophagy in postmortem autistic brain and mouse models. Her preliminary evidence indicates an association between mitochondrial defects and a dysregulation of mTOR-autophagy signaling in autistic brain. In mouse embryonic fibroblasts (MEFs) and neuronal cultures, mTOR hyperactivation inhibits autophagy, decreases mitochondrial membrane potential and causes an accumulation of damaged mitochondria. These results suggest that mitochondrial dysfunction in autism may result from aberrant mTOR- mediated mitophagy signaling. To address this hypothesis, Dr. Tang proposes 3 specific aims: 1) To determine whether mTOR hyper regulation inhibits neuronal mitophagy and causes mitochondrial dysfunction in ASD mouse models;2) To examine whether enhancing mitophagy rescues mitochondrial dysfunction in ASD mouse models; and 3) To confirm mitophagy defects in ASD postmortem brain and lymphoblasts. These data will be important for understanding the mechanism by which mTOR kinase regulates mitophagy, elucidating the mitochondrial pathophysiology that underlies ASD pathogenesis, and ultimately to design interventions effective in treatment. The knowledge and experience gained from this proposal will lead directly to a study of the effects of mitophagy defects and mitochondria dysfunction on synaptic pathology in autism, which will be proposed in an R01 grant application in 3-4 years of the award

Obesity & Autism

Briefly to return to obesity, since I just saw something interesting…

Since we know that over eating with increase mTOR and that hyper-activated mTOR in associated with several dysfunctions in autism, being obese and autistic is not a good idea.

In the US, where potent “psychiatric” drugs are widely prescribed for autism, almost a third of all adolescents with autism are obese, not just over-weight.  Weight gain is a known side effect of some of these drugs.

CDC Study Flags High Rate of Obesity among Teens with Autism

Conclusion

It would appear that hyperactivated mTOR in autism causes dysfunctions in autophagy/mitophagy.  This causes at least two subsequent dysfunctions:-

 ·        Synaptic pruning dysfunction.  There is a post all about this subject.

 Dendritic Spines in Autism – Why, and potentially how, to modify them

 ·        Mitochondrial dysfunction
 

If hyper activation of calpains is occurring in autism, this would explain some of the odd behaviour of Ca²⁺.  It would also again suggest Verapamil for a broader group of autism.

The numerous other connections between mTOR and autism, will be covered in upcoming post on mTOR, which will even include food intolerance. 

Human Growth Factors, Autism and the Centenarian Nobel Laureate

 

 

 



This post is another one of those long complicated ones, but should be worth reading.

We will look at Human Growth Factors, of which several have been identified by science and quite possibly more remain to be discovered.  Much of the science is well understood and overlaps with areas of interest to autism and another condition called Retts syndrome.

As often seems to be the case, elements of the science has been used by the anti-aging, athletic and body-building fraternities.

A surprise to me is that the science leads back to mast cells and that there some interesting therapeutic avenues already in existence.

We will even involve the seemingly obscure subject of amyloids that I introduced in a recent post.  In that post we discovered that in autism there were strange things going on with Amyloid Precursor Protein (APP).  I will postulate that perhaps amyloid-induced neuroinflammation might be a factor in the neuroinflammation found in autism.  In this post we will learn a potential strategy to control amyloid-induced neuroinflammation, which appears never to have tested in autism.

For a change we have some human interest, in the form of the Centenarian Nobel Laureate from Turin, Nerve Growth Factor and self-treated herself with it for 30 years, until she died aged 103, outliving her twin sister by 13 years.

We will look at:-

·        Human Growth Hormone (GH) and its replacement therapy

·        GABA and Baclofen that stimulate GH

·        Insulin-like Growth Factor 1 (IGF-1) and its replacement therapy

·        Nerve Growth factor (NGF) and its replacement therapy

·        Palmitoylethanolamide (PEA)

·        Brain-Derived Neurotropic Factor  (BDNF)

·        Neurotrophin-3

·        Neurotrophin-4

·        Why Rett Syndrome should not be confused with classic autism

 

That is quite a lot to digest in one post, but it is all interrelated and so should be together.

Basic Biology

As we have already discovered, the version of human biology in the textbooks is often a gross simplification of the reality.  Even in the up to date research papers it is clear that the understanding of human biology is constantly being revised.

For most people Human Growth Hormone, known as GH or HGH is the growth hormone.

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides Growth hormone-releasing hormone (GHRH or somatocrinin) and Growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus.

 

Source: Wikipedia

Main pathways in endocrine regulation of growth.

Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells.

Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms:

1.     Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.

2.     GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

Supplemental GH

Since 1995 Norditropin has been used in children and adults who have a natural deficiency in GH.  Usually it is used to treat a growth failure caused by low or no growth hormone.
 

In the 1990s it was popular in certain circles to use GH to look good and create a leaner body.  Harvard reported estimates that in 2004 20,000 to 30,000 Americans used GH as anti-aging therapy and another that 100,000 people received GH without a valid prescription in 2002.

The problem is that this seems to have been accompanied with side effects, ranging from strange growth effects in various parts of the body, to very early death.   It is much less popular today.

Safer ways to stimulate GH

There are numerous supplements sold that claim to stimulate GH and IGF-1.  These include GABA, Glutamine, Creatine and even Magnesium.

That the neurotransmitter GABA stimulates GH is a scientifically established fact.

Exercise itself stimulates the release of GH.

Some drugs are analogues of GABA, such as Gabapentin and Baclofen.  The GH stimulatory effect of Baclofen in particular has been well studied. 

Growth hormone response tobaclofen: a comparison of 10-mg and 20-mg doses in healthy men.

Here is a recent study still unpublished:-

Effect of Low-Dose Baclofen Administration on the GH-IGF1 Axis Study

For GABA to bind to GABA_B receptors   it is reported to depend on the presence of calcium or magnesium.  Magnesium is known to bind to and active GABA_B receptors  .

This might be another explanation for how magnesium supplements have a profound effect in some people with autism.  They comment on the affect of Mg on sensory overload.  In these people the activation of   GABA_B receptors  would explain this effect.

Quite possibly magnesium might increase/decrease the potency of Baclofen to stimulate GH; this perhaps should be tested.

Too much Baclofen or too much GH?

Baclofen is an analogue of the neurotransmitter GABA.  It is also an agonist for the GABA_B receptors.  As a drug it is primarily used to treat spasticity.

It now gets a little complicated, because within Baclofen are two isomers in equal amounts, R-Baclofen and S-Baclofen.

Isomers have the same chemical formula  C₁₀H₁₂ClNO₂ ^,  but the physical arrangement of the molecule is different and as a result their effect as a drug differs.

It appears that while R-baclofen is potent, the effect of S-Baclofen actually reduces the potency of R-baclofen.

The currently available forms of Baclofen, like Lioresal, from Novartis, is 50% R-Baclofen and 50% S-Baclofen.  So in a 10mg tablet you get 5mg of R-baclofen.  If you had a 5mg tablet of R-baclofen it would be many times more potent  than 10 mg of Lioresal.

This is all interesting, as is the development of Arbaclofen Placarbil, a Novel R-Baclofen prodrug.  This clever drug gets around the short half-life of R-Baclofen.  Drugs like Lioresal have to be taken 2-3 times a day, because the effect wears off fast.  Arbaclofen Placarbil slowly converts into R-Baclofen in the body and allows a much more even dose to be achieved.

Arbaclofen Placarbil, a Novel R-Baclofen Prodrug: Improved Absorption,Distribution, Metabolism, and Elimination Properties Compared with R-Baclofen 

Why so much detail?  Well, there was a very high profile trial in the US of Arbaclofen (R-Baclofen) in autism.  Overall the trial was seen as a failure, by sponsor Roche.  Among the trial group of children, there were some great responders, but there were others whose autism got much worse.

I really wonder if they monitored the level of GH in those kids.  Here is some data:- 

They were randomized 1:1 to Arbaclofen or placebo for 12 weeks. Drug doses ranged from 5 to 15 mg two or three times daily, with doses titrated to maximize CGI improvement. Most patients in the 5 to 11 age range ended up at 10 mg three times daily or, in the placebo group, the equivalent number of pills; most older patients received 15 mg three times daily or the placebo equivalent.

 

The older kids had 45mg a day of Arbaclofen.

In the literature the relative potency of R-Baclofen over Baclofen varies, but it is around 5+ times more strong.

This would equate to a dosage of 225mg of baclofen.  This is a HUGE dose.  Assuming it is only the R-Baclofen that stimulates GH, there would have been a massive increase in GH and the IGF-1.

There is something called “too much of a good thing”.  Perhaps the Arbaclofen non-responders were just suffering from a GH overdose.

In Fibromyalgia, the daily dose of Baclofen for adults recommended by Dr Jay Goldstein is 10 mg; so in a child with ASD, who either exhibited signs of Fibromyalgia or indeed spasticity (tense claw fingers or strange gait are quite common features in autism) such a dose would not seem unreasonable.  225g might seem excessive.

IGF-1

IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. A synthetic analog of IGF-1, mecasermin, is used for the treatment of growth failure.

IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion.

Not so simple.

So according to the textbooks IGF-1  is produced in the liver in response to GH.  IGF-1 can freely cross the BBB so therefore IGF-1 levels should be pretty much the same throughout the body and an increase in GH should always produce an increase in IGF-1;  only is does not always.

CIRCULATING INSULIN-LIKE GROWTH FACTOR (IGF)-1 REGULATESHIPPOCAMPAL IGF-1 LEVELS AND BRAIN GENE EXPRESSION DURING ADOLESCENCE

 

"Our results demonstrated that hippocampal IGF-1 protein concentrations during adolescence are highly regulated by circulating IGF-1, which were reduced by GH deficiency and restored by systematic GH replacement

 

Importantly, IGF-1 levels in the cerebral spinal fluid (CSF) were decreased by GH deficiency but not restored by GH replacement. Furthermore, analysis of gene expression using microarrays and RT-PCR indicated that circulating IGF-1 levels did not modify the transcription of IGF-1 or its receptor in the hippocampus but did regulate genes that are involved in microvascular structure and function, brain development, and synaptic plasticity, which potentially support brain structures involved in cognitive function during this important developmental period."

So the role and behavior of IGF-1  is much more complex than the textbook suggests.

How can low levels of IGF-1 in spinal fluid not be restored by GH replacement?

The above study was nothing related to autism, but it shows that the relationship between GH and IGF-1 in the brain, CSF and blood can be different.  Further it means that measuring IGF-1 in the blood does not necessarily indicate the level in the brain or the CSF. 

It appears that IGF-1 is very important to support normal brain function, but just because IGF-1 may be elevated in the blood actually tells you little with certainly about the level in the brain.

 

IGF-1 levels in autism

We already noted in previous post that IGF-1 levels are often elevated in autism.  Does this mean IGF-1 levels are also high in the brain?  It does  not.

Elevated levels of growth-related hormones in autism and autism spectrum disorder

 IGF-1 is already a trial therapy in autism and Retts syndrome; but Retts syndrome is very different to autism.  It is caused by is caused by mutations in the gene MECP2.  It affects almost exclusively girls.  Most important of all is that the growth factor most connected to Retts syndrome is not IGF-1, but its cousin Nerve growth Factor (NGF).

Insulin-like growth factor-1rescues synaptic and motor deficits in a mouse model of autism and developmental delay 

"We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology. Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD."

 

A Pilot Treatment Study of Insulin-Like Growth Factor-1 (IGF-1) in Autism Spectrum Disorder

"The proposed project will pilot the use of IGF-1 as a novel treatment for core symptoms of autism. We will use a double-blind, placebo-controlled crossover trial design in five children with autism to evaluate the impact of IGF-1 treatment on autism-specific impairments in socialization, language, and repetitive behaviors. We expect to provide evidence for the safety and feasibility of IGF-1 in ameliorating social withdrawal in children with Autistic Disorder. Further, we expect to demonstrate that IGF-1 is associated with improvement on secondary outcomes of social impairment, language delay, and repetitive behavior, as well as on functional outcomes of global severity."

You can supplement your natural IGF-1 with Increlex.  This is an approved therapy for growth delay.

It does appear that IGF-1 therapy looks safer than GH therapy.  There are very many stories of terrible consequences of GH abuse.

 

Nerve growth factor (NGF)

Professor Rita Levi-Montalcini discovered Nerve Growth Factor (NGF) in 1954 and she received the Nobel Prize in Physiology or Medicine in 1986 for the discovery.  She died in 2012 at the age of 103, having had a remarkable life.  She was also a pioneer in the area of mast cells, which it turns out are closely linked to NGF.

She spent much of her very long life researching the brain and concluded that to preserve her own mental capacity in old age she would need a little help. For her final the last 30 years she treated herself with home-made NGF eye drops, which she claimed restored her brain function to that of her youth.  It is notable that she outlived her twin sister by 12 years.  She never retired and in her 90s founded the European Brain Research Institute.

It seems many people have tried to copy her, but NGF is not so easy to obtain.

 

Nerve Growth factor (NGF) is a small secreted protein that is important for the growth, maintenance, and survival of certain target nerve cells. It also functions as a signaling molecule.  Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5).

NGF is critical for the survival and maintenance of sympathetic and sensory neurons. Without it, these neurons undergo apoptosis.  Nerve growth factor causes axonal growth. Studies have shown that it causes axonal branching and a bit of elongation. NGF binds with at least two classes of receptors: the p75 LNGFR (for "low-affinity nerve growth factor receptor") neurotrophin receptor (p75(NTR)) and TrkA, a transmembrane tyrosine kinase. Both are associated with neurodegenerative disorders.

There is evidence that NGF circulates throughout the entire body and is important for maintaining homeostasis.

 

“Normal” in autism but very low in Rett's

When researchers compared the level of NGF in spinal fluid in children with autism and Rett's Syndrome they found normal levels in autism by near negligible values in Rett's Syndrome, they even suggest that NGF be used as a test to discriminate Autism and Retts syndrome.

Levels of cerebrospinal fluidnerve-growth factor differ in infantile autism and Rett syndrome.

Abstract

Autism and Rett syndrome (RS) are both developmental disorders of unknown origin. Autism is a behaviorally defined syndrome. RS, which affects girls only, is characterized by a profound learning disability following early normal development, with a consistent cluster of clinical features. Differentiation of RS from infantile autism in the very early stages of the disorders is not always easy. Both syndromes still lack discriminative laboratory markers for accurate diagnosis and differentiation. We decided to compare the CSF nerve-growth factor (NGF) levels of children with infantile autism and children with RS using enzyme-linked immunosorbent assay (ELISA). Our findings of mainly normal CSF NGF in autism and low to negligible values in RS are in agreement with the different morphological and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. CSF NGF could be used as a biochemical marker for differentiation of patients with autism from those with RS.

This finding is confirmed when postmortem brain tissue from Retts was analysed. 

Reduced nerve growth factor in Rett's syndrome postmortem brain tissue.

One therapy currently being trialed in Rett's Syndrome is to give IGF-1 injections; perhaps they should also be trialing NGF injections. 

Normal in autism?  Not so fast

No studies have actually looked at NGF over time in autism and indeed the picture is far from simple. Research in 2013 looked at links between non-verbal communication deficits in people with autism and the gene that controls NGF.  The conclusion of the study was:-

 NGF is a promising risk gene for Non-verbal communication deficits.

Here is the full study:- 

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

 

"With regards to previously published genetic evidence supporting a role for NGF in ASD, none of the published GWAS or studies of structural variation have identified clear pathogenic variants in NGF in patients with ASD. However, a hypothesis-driven candidate-gene association study focusing on a variety of neuronal signaling pathways did identify evidence for association in the gene NTRK1, which is the canonical receptor for NGF. Remarkably, NTRK1 was one of only 2 out of approximately 60 genes that survived significance thresholds in the two cohorts investigated in that study. Combined with the current study, these data suggest the involvement of the NGF signaling pathway in ASD pathogenesis."

Also when children with ADHD were examines in research they were found to have elevated levels of NGF.

Serum nerve growth factor (NGF) levels in children with attentiondeficit/hyperactivity disorder (ADHD).

"Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder of childhood. The etiopathogeny of ADHD has not been totally defined. Recent reports have suggested a pathophysiological role of neurotrophins in ADHD. In this study, we evaluated serum levels of nerve growth factor (NGF) in patients with ADHD. The sample population consisted of 44 child or adolescent patients diagnosed with ADHD according to DSM-IV criteria; 36 healthy subjects were included in the study as controls. Venous blood samples were collected, and NGF levels were measured. The mean serum NGF levels of the ADHD patients were significantly higher than those of the controls. Age and gender of the patients were not correlated with serum NGF levels. There were no significant differences in NGF levels among the combined and predominantly inattentive subtypes of ADHD. Our study suggests that there are higher levels of serum NGF in drug naive ADHD patients, and that increased levels of NGF might have an important role in the pathophysiology of ADHD." 

This would imply to me that NGF is indeed very much implicated in autism.  In one piece if research NGF was normal in autism, but the authors of the QTL are suspicious of this.  Since ADHD is so overlapping with autism, the above paper really points to the need to go back and do a more rigorous study on NGF and autism.  For now, I will assume that NGF is indeed elevated in autism at some point. 

Here is rather complex paper that goes into great depth regarding the therapeutic potential of NGF and BDNF:- 

NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines.

"Thus, it was remarkable to discover that treatment of newborn rats with NGF caused a systemic increase in the number of mast cells Today there is compelling evidence that NGF, in addition to its neurotropic function, enhances survival and activity of a large number of nonneuronal cells, including immune cells, pancreatic beta cells, vascular smooth muscle cells, cardiomyocytes, endothelial cells, epithelia cells, and adipocytes.

The secretory proforms of NGF and BDNF, pro- NGF and pro-BDNF (40), respectively, are cleaved extracellularly through the tissue type plasminogen activator (tPA)-serine protease plasmin pathway; note that today’s widely administrated cholesterol-lowering drugs, collectively named statins, can induce tPA
 

Indeed, NGF and BDNF initially discovered as neural growth factors are also affecting (i) immune cells, (ii) blood vessels/angiogenesis , (iii) synaptic plasticity and consolidation  involved in learning and memory , (iv) wound healing and tissue repair, and (v) glucose, lipid, antioxidant and energy metabolism.

 

Therapy Insight

NGF- and BDNF-based therapeutic pipeline for neuropsychiatric diseases discussed herein (except migraine, cluster headache, and probably epilepsy) may

include (i) applying NGF itself , (ii) targeting the secretory and signaling pathways using existing or novel drugs, (iii) TrkB transactivation , (iv) ampakines, small molecules that stimulate Alpha-amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid (AMPA)-type glutamate receptors , (v) selective deacetylase inhibitors, and (vi) “brain food”, that is, neuroprotective nutrients including calorie restriction, also physical activity .Whereas a high-fat diet reduces brain BDNF levels and declines cognitive capacity. Accordingly, the above mentioned classes of drugs, including calorie restriction mimetics – see, for example,O’Brian and Chu and Nikolova  for resveratrol –, require a novel research evaluation as possible pharmaceuticals and nutraceuticals also for cardiometabolic diseases. Meanwhile, NGF and BDNF could be reasonable targets for resveratrol’s therapeutic effects in both neuropsychiatric and cardiometabolic diseases. Further, recent findings have discovered that free fatty acids may influence brain development through binding to G protein- coupled receptor-40 expressed in the hippocampus (151). Interestingly, some widely used drugs for cardiometabolic diseases such as the cholesterol-lowering statins and peroxisome proliferatoractivated receptor gamma agonists as well as two novel common players, acetylcholine and glucagon like peptide-1, have been introduced into diabetes-obesity-dementia link . Another crossroad of nerves and adipose tissue may be adipose-derived mesenchymal stem cells, which can differentiate into neurons in BDNFenriched cultures, and thus representing useful tool to treat neuropsychiatric disorders. Note that pro-NGF can be cleaved proteolytically at dibasic residues and liberates two other peptides beside NGF, LIP1, a 29 amino acid (aa) peptide, and LIP2, a 38 aa peptide; their synthetic forms may be targets for new drugs in NGF-related diseases.

The challenge for the future is to understand to what extent the effects of NGF and BDNF are interrelated with regards to their neuro-, synapto-, vasculoand metabotrophic potentials. Further studies should provide answers to the questions of when and how NGF-BDNF/TrkA,B dysfunction appears and leads to both neuropsychiatric and cardiometabolic diseases. It  is hope that by bringing the datasets together in these seemingly diverse disorders we can help develop a conceptual novel basis for future studies in the field.

 

So NGF can be both good and bad.  It looks like statins will stimulate bother NGF and BDNF. Older people and anyone with Retts Syndrome are likely to benefit from more NGF.  In autism it appears possible that there was too much NGF and BDNF at a very early age, with levels then changing.  High levels of NGF and BDNF look a bad idea.  A lot more research is needed to understand what determines  NGF and BDNF levels.  It appears that BDNF may stay high in autism, but NGF levels.
 

NGF therapy

You will naturally be wondering if you can order some NGF with your PayPal account, sadly not.

Rita probably made here NGF eye drops in her kitchen.

An Italian firm called Dompé has recently succeeded in developing a process for the industrial production of recombinant human NGF (rhNGF) at its biotech plant in Italy, and they are in the process of getting NGF eye drops approved as a drug for the treatment of disorders of both the anterior and posterior segments of the eye, including dry eye and glaucoma.

We all know that Rita had entirely different reasons to use her NGF eye drops.

I do like it when scientists/doctors very occasionally doing interesting things like self-experimentation; it shows they have ultimate faith in their own ideas.  I also like it when they use novel methods to deliver the drug into the body.  Eye drops and nasal sprays mean no loss via gut and no issue with passing through into the blood supply and are much more favorable than injections.  It also seems, from both Rita, the Nobel Laureate and Jay Goldstein, the Fibromyalgia doctor, that mixing up your nasal spray or eye drops is simple, effective and cheap.

Back again to Rita - Countering the pro-inflammatory actions of NGF

Mast cells

First Professor Rita Levi-Montalcini discovered that Mast cells synthesize, store, and release nerve growth factor and then her group discovered in 1993 that Palmitoylethanolamide (PEA) acts as a natural modulator of hyperactive mast cells, counteracting the pro-inflammatory actions of NGF.
 

Mast cells synthesize, store,and release nerve growth factor 

Professor Rita Levi-Montalcini on Nerve Growth Factor, Mast Cellsand Palmitoylethanolamide, an Endogenous Anti-Inflammatory and Analgesic Compound

Professor Levi-Montalcini’s focus was on NGF, and already as early as 1977 she pointed out that NGF was an irritative compound inducing mast cell degranulation . The relation between mast cell and NGF, also related to their interactive function in diseases, were topics Rita Levi-Montalcini worked on for many years

“...Unregulated mast-cell activation constitutes a considerable risk to the health of the organism, and it is not unreasonable to expect that nature should have devised a means for the host to defend itself against such damage. It has recently been proposed that saturated N-acyl-ethanolamides like palmitoylethanolamide, which accumulate in tissues following injury and which down modulate mast-cell activation in vitro, exert a local, autacoid, and anti-injury function via mast cells. Palmitoylethanolamide is orally active in reducing tissue inflammation and mast cell degranulation in vivo, in decreasing hyperalgesia that accompanies peripheral nerve compression, and in limiting the neurological deficits of experimental allergic encephalomyelitis. Moreover, palmitoylethanolamide appears to project against excitotoxic neuronal death in vitro and to be produced by cultured CNS neurons upon excitatory amino acid receptor activation. The mechanism of this action of N-acylethanolamides has been termed autacoid local injury antagonism (ALIA).”

 

Based on her work in the 90s PEA is now available as a nutraceutical for indications related to chronic pain and chronic inflammation. PEA has been explored in a variety of indications such as sciatic pain, diabetic pain, neuropathic pain, pain due to arthritis and pain in multiple sclerosis in the period 1992-2010 and around 20 clinical trials have documented its safety and efficacy in these chronic pain states. In the period 1970-1980 its safety and efficacy was already documented in a series of double blind clinical trials in flu and respiratory infections. PEA is therefore most probably the best-documented nutraceutical around, with pharmacological profile described in more than 350 scientific papers 

“...palmitoylethanolamide may behave as local autacoids capable of negatively modulating mast cell activation (ALIA mechanism). In keeping with this hypothesis, palmitoylethanolamide reduces mast cell activation associated with inflammatory processes. With these considerations in mind, the described pharmacological effects of palmitoylethanolamide could be mediated by interactions with CB2 receptors on mast cells.”

 

Professor Levi-Montalcini’s focus was on NGF, and already as early as 1977 she pointed out that NGF was an irritative compound inducing mast cell degranulation. The relation between mast cell and NGF, also related to their interactive function in diseases, were topics Rita Levi-Montalcini worked on for many years

“...Unregulated mast-cell activation constitutes a considerable risk to the health of the organism, and it is not unreasonable to expect that nature should have devised a means for the host to defend itself against such damage. It has recently been proposed that saturated N-acyl-ethanolamides like palmitoylethanolamide, which accumulate in tissues following injury and which down modulate mast-cell activation in vitro, exert a local, autacoid, and anti-injury function via mast cells. Palmitoylethanolamide is orally active in reducing tissue inflammation and mast cell degranulation in vivo, in decreasing hyperalgesia that accompanies peripheral nerve compression, and in limiting the neurological deficits of experimental allergic encephalomyelitis. Moreover, palmitoylethanolamide appears to project against excitotoxic neuronal death in vitro and to be produced by cultured CNS neurons upon excitatory amino acid receptor activation. The mechanism of this action of N-acylethanolamides has been termed autacoid local injury antagonism (ALIA).”

 "Prof. Rita Levi-Montalcini is widely known for her work on NGF. Much less is known about two other formidable chapters she added to neurobiology: the central role of the mast cell in much pathology, and the modulating role of the endogenous lipid PEA via the mast cell. Based on her work in the 90s PEA is now available as a nutraceutical for indications related to chronic pain and chronic inflammation. PEA has been explored in a variety of indications such as sciatic pain, diabetic pain, neuropathic pain, pain due to arthritis and pain in multiple sclerosis in the period 1992-2010 and around 20 clinical trials have documented its safety and efficacy in these chronic pain states. In the period 1970-1980 its safety and efficacy was already documented in a series of double blind clinical trials in flu and respiratory infections. PEA is therefore most probably the best-documented nutraceutical around, with pharmacological profile described in more than 350 scientific papers"

 

Reducing Amyloid-Related Brain Damage

In an earlier posts we looked at Amyloids in the brain in autism and Alzheimer’s.  There was a distinct difference in what was going on and definitely worse things were happening in Alzheimer’s, but things were far from normal in autism.

http://epiphanyasd.blogspot.com/2013/12/amyloids-app-adam17-and-autism.html

Several papers have demonstrated that an imbalance of the endocannabinoid system (ECS) and alterations in the levels of PEA occur in acute and chronic inflammation. For instance during β-amyloid-induced neuroinflammation the deregulation of cannabinoid receptors and its endogenous ligands accompanies the development and progression of disease.

Palmitoylethanolamide Protects Against the Amyloid-β25-35-Induced Learning and MemoryImpairment in Mice, an Experimental Model of Alzheimer Disease

The study strongly suggests that people with Alzheimer’s would benefit from the neuroprotective effects.  PEA also reduced Amyloid-Induced Oxidative Stress.
 

PEA as an anti-epileptic

Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice

Abstract

PURPOSE:

The purpose of this study was to evaluate in mice the anticonvulsant potential of N-palmitoylethanolamide, a putative endocannabinoid that accumulates in the body during inflammatory processes.

METHODS:

N-palmitoylethanolamide was injected intraperitoneally (i.p.) in mice and evaluated for anticonvulsant activity [in maximal electroshock seizure (MES) and chemical-induced convulsions] and for neurologic impairment (rotorod). It was compared with anandamide and with different palmitic acid analogues as well as with reference anticonvulsants (AEDs) injected under the same conditions.

RESULTS:

The MES test showed, after i.p. administration to mice, that N-palmitoy]ethanolamide had an median effective dose (ED50) value comparable to that of phenytoin (PHT; 8.9 and 9.2 mg/kg, respectively). In the subcutaneous pentylenetetrazol test and in the 3-mercaptropropionic acid test, it was effective only against tonic convulsions. N-palmitoylethanolamide was devoid of neurologic impairment < or = 250 mg/kg, yielding a high protective index.

CONCLUSIONS:

N-palmitoylethanolamide, an endogenous compound with anti-inflammatory and analgesic activities, is a potent AED in mice. Its precise mechanism of action remains to be elucidated.

 
 

Disease-Modifying Agent in Peripheral Neuropathy

We have found before that what is good for treating Peripheral Neuropathy, can also be useful in treating autism.  Anybody remember those posts on antioxidants?  The antioxidants helped reduce diabetic neuropathy and even reduced the amount of insulin people needed, which means something must have happened to improve pancreatic function.  Some people’s autism is apparently linked to pancreatic dysfunction, if you did not know.

Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism Researchers discover a way to boost levels of palmitoylethanolamide

 
All in all  PEA has been shown to have anti-inflammatory, anti-nociceptive, neuroprotective, and anticonvulsant properties.  Where can I get some?

 

PEA (palmitoylethanolamide) levels in autism and ADHD

Very helpfully, some researchers in Japan have already done a study to measure the levels of PEA in autism and ADHD.

Decreased beta-phenylethylamine inurine of children with attention deficit hyperactivity disorder and autistic disorder

Beta-phenylethylamine (PEA), a biogenic trace amine, acts as a neuromodulator in the nigrostriatal dopaminergic pathway and stimulates the release of dopamine. To clarify the mechanism of neurochemical metabolism in attention deficit hyperactivity disorder (ADHD), we measured the urine levels of PEA using gas chromatography-chemical ionization-mass spectrometry. The urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), homovanillic acid (HVA), and 5-hydroxy-indoleacetic acid (5-HIAA) were determined by high performance liquid chromatography. Urine samples were collected in a 24 hour period. Findings were compared with those obtained from controls (N = 15), children with ADHD (N = 15), and children with autistic disorder (AD) (N = 5). The mean urinary levels of MHPG, HVA, and 5-HIAA in the children with ADHD were not significantly different from those of the controls or those with AD, whereas PEA levels were significantly lower in children with ADHD (11.23 +/- 13.40 micrograms/g creatinine) compared with controls (56.01 +/- 52.18 micrograms/g creatinine). PEA and MHPG levels in children with AD (14.75 +/- 14.37 micrograms/g creatine, 1.10 +/- 0.61 micrograms/mg creatine, respectively) were significantly decreased compared to controls (MHPG, 2.2 +/- 0.9 micrograms/mg creatine). The decreased urine PEA in children with ADHD and AD may suggest a common underlying pathophysiology. The decreased urine MHPG in children with AD might indicate the existence of an alteration in central and peripheral noradrenergic function.

This is pretty much as expected and of course does prompt the question of how to raise PEA levels, if PEA is such a handy and helpful molecule.

Boosting the level of PEA

Some of the literature suggests that oral administration of PEA will be rather ineffective, since not much will reach the brain.  On the other hand there are plenty of studies showing PEA is more effective than conventional pain killers, so it must be reaching the brain.

Research indicates that PEA is deactivated by a special protein (N-acylethanolamine-hydrolyzing acid amidase) and it is possible to block the action of this protein and hence raise the level of PEA.addition, they found that PEA - also present in foods like eggs and peanuts - is deactivated by a protein called N-acylethanolamine-hydrolyzing acid amidase, which is an enzyme that breaks down molecules controlling cell inflammation

In addition, they found that PEA - also present in foods like eggs and peanuts - is deactivated by a protein called N-acylethanolamine-hydrolyzing acid amidase, which is an enzyme that breaks down molecules controlling cell inflammation.

The full paper is here:-

Selective N-acylethanolamine-hydrolyzing acidamidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation

A cynic would point out that since PEA cannot be patented – it is naturally occurring substance – the pharmaceutical industry would prefer to find a patentable substance, to be the adopted therapy, rather than PEA itself.

In the meantime the logical way forward would be just to eat some.  Well, dark chocolate is rich in PEA, but you might have to eat quite a lot of it.  The alternative is a pill.  There is quite a choice:-

http://palmitoylethanolamide4pain.com/about-2/

If you want to buy in bulk you get a discount:-

http://www.rs4supplements.com/en/home

 

Brain-Derived Neurotrophic Factor  (BDNF)

Unusually high levels of the signaling peptide BDNF, or brain-derived neurotropic factor, have been detected in blood samples from children with autism

During brain development, BDNF regulates the birth and differentiation of brain cells, or neurons. Some of BDNF’s target cells, such as cortical interneurons, which transmit information between different layers of the brain cortex, have been implicated in autism. BDNF is also a regulator of brain growth, and children with the disorder tend to have abnormally large brains during early development. What’s more, MeCP2, a gene in which mutations are known to cause the autism-related Rett syndrome, directly regulates the expression of BDNF.

If high BDNF levels do prove to be a cause of the disorder, drugs that block its production or signaling might be an effective treatment for autism.

Misregulation of BDNF in autism spectrum disorders

Is autism caused by early hyperactivity of brain-derived neurotrophic factor?

BDNF is down regulated by stress and up regulated by learning, antidepressants, histone deacetylase inhibitors, physical activity, and dietary calorie restriction

 

Altered Cytokine and BDNF Levelsin Autism Spectrum Disorder

 

Neurotrophin-3

Although the vast majority of neurons in the brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells; a process known as neurogenesis. Neurotrophins are chemicals that help to stimulate and control neurogenesis.

NT-3 is unique in the number of neurons it can potentially stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC and TrkB - see below).

 

Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism.

Autism is a neurodevelopmental disorder characterized by social and language deficits, ritualistic-repetitive behaviors and disturbance in motor functions. Data of imaging, head circumference studies, and Purkinje cell analysis suggest impaired brain growth and development. Both genetic predisposition and environmental triggers have been implicated in the etiology of autism, but the underlying cause remains unknown. Recently, we have reported an increase in 3-nitrotyrosine (3-NT), a marker of oxidative stress damage to proteins in autistic cerebella. In the present study, we further explored oxidative damage in the autistic cerebellum by measuring 8-hydroxydeoxyguanosine (8-OH-dG), a marker of DNA modification, in a subset of cases analyzed for 3-NT. We also explored the hypothesis that oxidative damage in autism is associated with altered expression of brain neurotrophins critical for normal brain growth and differentiation. The content of 8-OH-dG in cerebellar DNA isolated by the proteinase K method was measured using an enzyme-linked immunosorbent assay (ELISA); neurotrophin-3 (NT-3) levels in cerebellar homogenates were measured using NT-3 ELISA. Cerebellar 8-OH-dG showed trend towards higher levels with the increase of 63.4% observed in autism. Analysis of cerebellar NT-3 showed a significant (p = 0.034) increase (40.3%) in autism. Furthermore, there was a significant positive correlation between cerebellar NT-3 and 3-NT (r = 0.83; p = 0.0408). These data provide the first quantitative measure of brain NT-3 and show its increase in the autistic brain. Altered levels of brain NT-3 are likely to contribute to autistic pathology not only by affecting brain axonal targeting and synapse formation but also by further exacerbating oxidative stress and possibly contributing to Purkinje cell abnormalities.

 

Neurotrophin-4

Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the NTF4 gene.

It seems that NT-4 levels are elevated in cases of mental retardation and not in cases of autism. 

 Serum neurotrophin concentrations in autism and mental retardation: a pilot study.

Abstract

To evaluate the availability of the serum neurotrophins for the diagnosis of the patients with neurodevelopmental disorder, we measured the serum concentration of brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) in the patients diagnosed with autism (n=18) and mental retardation (n=20), or healthy controls (n=16), using enzyme-linked immunosorbent assay. There tended to be a higher concentration of serum BDNF found in the autistic group (P<0.05 by analysis of variance (ANOVA)) and the mental retardation group (P<0.001 by ANOVA) compared to the control group. Serum NT-4 concentration tended to be increased in the mental retardation group (P<0.05 by ANOVA). We conclude that measuring the serum concentration of two neurotrophins, BDNF and NT-4, might be helpful to diagnose or classify disorders such as autism or mental retardation.

 

 

Conclusion (finally)

After all that information there are some useful conclusions. Slightly raising GH by stimulating the body to produce more, looks much smarter than GH therapy, unless it is absolutely necessary.  The extra GH in most cases should stimulate more IGF-1, but not necessarily where it is needed.  IGF-1 therapy itself looks interesting but currently involves needles.  An oral IGF-1 related analogue has Orphan Drug status in the US and Europe and that may prove very useful, when it becomes available.

If Rett’s Syndrome is the concern, it looks like NGF really is needed ASAP. Rita Levi-Montalcini found a way to treat herself with NGF more than 30 years ago.

As a treatment for cognitive decline, NGF looks very interesting.  I wonder what the effect would be on apparent Mental Retardation, if given young enough.  Perhaps NGF should be measured in cases of suspected MR?

PEA looks very interesting for those who believe Theoharides’ Autism as an Allergy of the Brain hypothesis.  It also looks interesting as a safe pain reducing therapy to test in fibromyalgia and mastocytosis.  PEA also has anti-epileptic properties and in this blog we have seen a great deal can be learnt from thinking about the comorbidities of autism.  PEA might well eventually find a place in my “Autism Toolkit”, if it stabilizes mast cells.  It is quite strange that nobody has investigated the benefit of PEA in a controlled trial on kids with ASD, there are several possible mechanisms whereby it could be helpful.  PEA does not need a doctor’s prescription.

It looks like high NT-3 levels are a result of autism and ongoing oxidative stress in the brain; another reason to treat oxidative stress.

It appears likely that autism is accompanied by an excess of Brain-Derived Neurotropic Factor and if ongoing research proves this, then therapies that block its production or signaling might be an effective treatment for autism.