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.
Here is a
recent study still unpublished:-
For GABA to
bind to GABAB
receptors it is reported
to depend on the presence of calcium or magnesium. Magnesium is known to bind to and active GABAB 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 GABAB
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 GABAB 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.
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.
"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.
"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."
"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.
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.
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:-
"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.
"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:-
"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.
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).”
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.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.
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
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.
The full paper is here:-
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:-
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.
BDNF is down regulated by stress
and up regulated by learning, antidepressants, histone deacetylase inhibitors,
physical activity, and dietary calorie restriction
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).
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.
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.
