There is no
doubt that most parents’ ideal autism therapy would be a special diet. The most popular diet is the gluten and
casein free diet; in a sub-type of autism this diet clearly is very effective.
Another very interesting diet is the Ketogenic diet and its easier to implement
cousin, the Modified Atkins diet. There
is also the GAPS diet.
Many
scientists are very skeptical of the therapeutic value of special diets.
I am always
looking for connections in the science.
If I can find from multiple starting points the same conclusion, this
triggers my interest, regardless if anyone else has highlighted the area as an
issue for autism.
Today my reinforcing arguments is indeed a diet; the Ketogenic diet.
Remember
that epilepsy is highly comorbid with autism, and trials have shown the
ketogenic diet to reduce the incidence of seizures by half.
This post
was supposed to be a short one, but it just kept growing. You can skip the complicated parts and go to
the conclusions.
Ketogenic Diet
The ketogenic diet is a
high-fat, adequate-protein, low-carbohydrate diet that in medicine is used
primarily to treat difficult-to-control epilepsy in children. The diet forces
the body to burn fats rather than carbohydrates. Normally, the carbohydrates
contained in food are converted into glucose, which is then transported around
the body and is particularly important in fuelling brain function. However, if
there is very little carbohydrate in the diet, the liver converts fat into fatty
acids and ketone bodies. The ketone bodies pass
into the brain and replace glucose as an energy source. An elevated level of
ketone bodies in the blood, a state known as ketosis, leads to a
reduction in the frequency of epileptic seizures.
The original therapeutic diet for paediatric epilepsy provides just enough
protein for body growth and repair, and sufficient to maintain the correct
weight for age and height. This classic ketogenic diet contains a 4:1 ratio by
weight of fat to combined protein and carbohydrate. This is achieved by
excluding high-carbohydrate foods such as starchy fruits and vegetables, bread,
pasta, grains and sugar, while increasing the consumption of foods high in fat
such as cream and butter.
Modified Atkins
First reported in 2003, the idea of using a form of the Atkins diet to treat
epilepsy came about after parents and patients discovered that the induction
phase of the Atkins diet controlled seizures. The ketogenic diet team at Johns
Hopkins Hospital modified the Atkins diet by removing the aim of achieving
weight loss, extending the induction phase indefinitely, and specifically
encouraging fat consumption. Compared with the ketogenic diet, the modified
Atkins diet (MAD) places no limit on calories or protein, and the lower overall
ketogenic ratio (approximately 1:1) does not need to be consistently maintained
by all meals of the day. The MAD does not begin with a fast or with a stay in
hospital and requires less dietitian support than the ketogenic diet.
Carbohydrates are initially limited to 10 g per day in children or 20 g per day
in adults, and are increased to 20–30 g per day after a month or so, depending
on the effect on seizure control or tolerance of the restrictions. Like the
ketogenic diet, the MAD requires vitamin and mineral supplements and children
are carefully and periodically monitored at outpatient clinics.
The modified Atkins diet reduces seizure frequency by more than 50% in 43%
of patients who try it and by more than 90% in 27% of patients. Few adverse
effects have been reported, though cholesterol is increased and the diet has
not been studied long term.
Why does ketosis reduce seizures?
For a change,
Wikipedia cannot tell you why ketosis is good for epilepsy.
If you look
deeper in the research you can find a very good likely reason why it may be so
effective; we have yet another tongue twister, Peroxisome
proliferator-activated receptor alpha, known as PPARα.
It is PPARα which is the
connection to my early post all about growth factors in autism. It is my belief
that Growth Hormone (GH) and its related growth factors are of key importance
in understanding and treating autism. In that very lengthy post I introduced PEA
(Palmitoylethanolamide) as an interesting substance that, amongst other things,
modulates the release of nerve growth factor (NGF) from mast cells. PEA has been extensively researched and has
interesting effects including treating pain, inflammation and indeed epilepsy.
I started to look into how PEA works and to see what that
mechanism might be. After a dead end
looking at Endocannabinoids, I found what I was looking for – PPARα.
PEA - Pain Relief and
Neuroprotection Share a PPARα
-Mediated Mechanism
So it
appears there is an interesting connection linking the apparently successful
Ketogenic diet, and the supplement PEA.
The Ketogenic diet does have some side effects and drawbacks; apparently
PEA has no side-effects or contra-indications.
Another interesting
point is that a diet very rich in olive oil has been shown to have the benefits
of the Ketogenic diet and olive oil directly raises
oleylethanolamide (closely related to palmitoylethanolamide) and also a PPARα
activator.
Peroxisome
proliferator-activated receptor alpha
PPAR-alpha is a transcription factor and a major regulator of lipid
metabolism in the liver. PPAR-alpha is activated under conditions of
energy deprivation and is necessary for the process of ketogenesis, a key adaptive
response to prolonged fasting. Activation of PPAR-alpha promotes uptake,
utilization, and catabolism of fatty acids by upregulation of genes involved in
fatty acid transport, fatty binding and activation, and peroxisomal and
mitochondrial fatty acid β-oxidation. PPAR-alpha is primarily activated through
ligand binding. Synthetic ligands include the fibrate drugs, which are used to treat hyperlipidemia, and a diverse
set of insecticides, herbicides, plasticizers, and organic solvents
collectively referred to as peroxisome proliferators. Endogenous ligands
include fatty acids and various fatty acid-derived compounds.
You may
recall from earlier post that in autism there appears to be strange things
going on with the lipid mechanism. Here
is a paper for those interested:-
PPARα and the ketogenic diet (and cancer)
The
following paper does cover the role of PPARα
in the ketogenic diet (KD) but its main thrust is the use as a cancer
therapy. We have already come across
other autism drugs that have potential in cancer therapy. NAC was shown to be beneficial in cases of
both prostate cancer and breast cancer.
I know some readers are
also interested in some forms of cancer, so I have included the cancer part. Others may want to skip this part.
Calorie restricted
KetoCal diet significantly decreased the intracerebral growth of both tumor
types
and decreased the intratumoral microvessel density. Implementation of this diet resulted in
elevation of plasma concentrations of ketone bodies, which might trigger the
energetic imbalance in the tumors, since tumor tissue showed reduced activity
of the enzymes required for ketone body oxidation: hydroxybutyrate
dehydrogenase and succinyl-CoA: 3- ketoacid-CoA transferase comparing to
conlateral normal brain tissue. Moreover, in some cases of advanced malignant tumors (anaplastic
astrocytoma and cerebellar astrocytoma),
patients respond well to CRKD dietary regimen. The question about the safety
of CRKD in patients who are likely to develop cachexia due to tumor burden may
arise, nevertheless malnutrition or undernourishment have not been reported.
Remarkably, ketogenic
diet is also beneficial for patients with neurological disorders, especially in
epilepsia.
The first observations revealed that starvation – mimicking diet, and CRKD in
particular, have anti-seizure properties. Further investigation stated that
both high fat content and reduced total caloric intake are important because they
induce hormonal responses favoring ketogenesis: low insulin and high glucagon,
as well as increased cortisol blood levels promote acetyl-CoA conversion to ketone bodies and
release to circulation. Increase
in blood fatty acid concentration, which physiologically activates PPAR α,
was observed in CRKD as a result of fat reserves mobilizationand high fat intake
Fig. (3). Ketone bodies
are avidly consumed by brain tissue during glucose deprivation. In limited
glucose availability, astrocytes protect neurons from the energetic stress by
performing fatty acid oxidation and ketogenesis and supply the surrounding
neurons with ketone bodies. Ketone bodies are prioritized energetic substrates
and they are metabolized before glucose and free fatty acids. Their cellular
uptake is mediated by monocarboxylate transporter MCT1, which transcription is
positively regulated by PPAR. Importantly, both endogenous (free fatty acids)
and synthetic PPARα ligands are free to
flow through the blood-brain barrier and they may reach high levels in the
brain tissue. In addition to the role in brain tumors, ketogenesis may also
become a prognostic factor in colon carcinoma. 3-Hydroxy-3-methylglutaryl-CoA
synthase is severely downregulated by c-Myc in colon cancer cell lines with
high activity of Wnt/ -catenin/ T
cell factor 4 (TCF-4)/ c-Myc pathway. Ketogenic capability and HMGCS expression
levels are positively correlated with enterocyte differentiation and decreased
in colon or rectal carcinomas, especially those poorly differentiated.
In theory, PPAR α activation could counteract c-Myc induced
alterations of mitochondrial metabolism by restoring the HMGCS and ketogenesis
levels and by inhibiting glutaminolysis through transcriptional repression of
the two enzymes crucial for this pathway: glutaminase and glutamate dehydrogenase.
Moreover, PPAR α and pan-PPAR agonists like bezafibrate stimulate oxidative hosphorylation and respiratory capacity by
inducing PGC-1 mediated
mitochondrial biogenesis. Although this activity goes in line with c-Myc
action, which was reported to stimulate mitochondrial proliferation, this could cause either normalization of
cancer cell energetic balance or induce a 'metabolic catastrophe' in the cells
with genetically impaired mitochondrial function.
Recent studies on mice bearing different tumors revealed that
dietary restrictions do not affect those with constitutive activation of
PI3K/Akt pathway. Other cancer characterized by transformed HRAS/ KRAS, BRAF or with loss of
TP53,
show
a significant decrease of the growth rate and increased apoptosis when the host
animals were subjected to dietary restriction. Resistance to dietary
restriction depended on the Akt phosphorylation status and its activation,
which lead to FOXO1 phoshorylation and cytoplasmic sequestration. When arrested
in the cytoplasm, FOXO1 is unable to exert its proapoptotic functions. There
are several proteins that negatively affect Akt activity, namely protein
phosphatases PTEN, SHIP and PPA2 that directly dephoshorylate Akt; and TRB3
(mammalian homolog of Drosophila protein tribbles), a protein
that binds to Akt and blocks its phosphorylation. TRB3 expression in liver
rises during fasting and is driven by PGC-1 in PPAR α dependent manner, as there are
functional PPRE elements in the TRB3 promoter. Metabolic function of TRB3 is to
block insulin dependent Akt activation in fasting, in parallel to PGC-1 / PPARα induced
gluconeogenesis and fatty acid oxidation. This seems to be a part of a SIRT1/ LKB1/
AMPK/ PGC-1 pathway which
constitutes an adaptive response to CR, because in mice with muscle – specific LKB1 knockout in
which the PGC-1, PPAR α and TRB3 were
severely decreased. Interestingly, TRB3 upregulation in lymphocytes is induced
by fibrates in PPAR α independent fashion with utilization of C/EBP and C/EBP homologous proteins.
Therefore it is reasonable to speculate that pharmacological
PPAR activation
together with CRKD might improve the anticancer outcome in case of dietary
restriction resistant tumors with overactive PI3K or nonfunctional PTEN. The
situation would probably be different in tumors with
constitutively active plasma membrane associated Akt mutants (with
activating Akt mutations or in model systems with the introduction of
myristoylated Akt), as in these cases TRB3 possibly would not affect the already
phosphorylated Akt.
Although these hypotheses need to be verified, the negative influence
of TRB3 on Akt phosphorylation seems to be a general phenomenon.
7. CONCLUSION
PPAR α
activators have a great potential of supplementing conventional anticancer
therapies by modulating cancer cell energy metabolism and signaling pathways. This notion is
based on multiple observations, which include PPAR α-mediated
inhibition of two prominent oncogenes: c-Myc and Akt Fig. (3). In this
inhibitory action, PPAR α suppresses glutaminolysis and
glutamine catabolism in mitochondria, as well as activates ketogenesis by
promotion of fatty acid oxidation and transactivation of HMGCS. In cancer cells
these processes are c-Myc regulated. Next, PPAR actions slow down glycolysis by inhibiting Akt and blocks
Akt induced fatty acid synthesis by repressing PDH activity in mitochondria
via PDK4 upregulation. Finally PPAR α functionally cooperates
with AMPK, SIRT1 and PGC-1 in regulating the
cellular response to calorie restriction. In perspective, it would be important
to elucidate the details of possible interplay between these regulatory
proteins, and to verify the role of PPAR α activation in the of CRKD applied to in vivo cancer models. Of
note, the potential use of clinically tested synthetic ligands for PPAR α against cancer, although seems to be a straightforward
and fairly safe procedure, it still requires our careful consideration. There
are still debates over fibrate drugs safety and three main caveats have been
are presented : (1) fibrate ability to bind hemoglobin which reduces its
affinity to oxygen; (2) fibrates may disrupt mitochondrial electron transfer
chain particularly by inhibiting complex I; and (3) fibrates induce
mitochondrial ROS production. These potentially harmful activities are
presently understood to be receptor-independent, which implies the need for new
generation of PPAR α ligands which would possess improved physiological and
pharmacological characteristics.
“The roles of PPARs in brain and, more
specifically, the functional consequences of PPARα activation, have been
discussed previously. PPARα plays a key role in regulating ketogenesis (an
obvious hallmark of the KD) and a more extended role in regulating hepatic
amino acid metabolism with the potential consequences on neurotransmitter
concentrations if PPARα is activated within brain .”
“There is now increased understanding
of the KD and the implications for the actions of small molecule
anticonvulsants that interact with PPARα. Especially, with the emerging
evidence that PPARα is expressed at low but functionally significant levels in
many nerve cells throughout the body, the possibility exists for common modes
of action of different anticonvulsants in spite of their differential
seizure-type efficacy. For example, although valproate, palmitoylethanolamide,
and the KD have a limited overlap in seizure-type efficacy, they may still
share a common mechanism of action, taking into account their
pharmacodynamic/pharmacokinetic differences acting on a common but widely
distributed molecule such as PPARα”
PPARα and the high olive oil diet
“However, a recent report shows that a
30% fat diet enriched in olive oil directly raises oleylethanolamide (closely
related to palmitoylethanolamide and also a PPARα activator) within rat brain.
Thus, modifications to the fatty acid profile of the much higher (80%) classic
ketogenic diet may also be predicted to directly modify PPARα-activating
molecules in brain, potentially providing a broader spectrum of anticonvulsant
effect.”
The above actually refers to rats, but here is the
abstract of that paper:-
Abstract
Endocannabinoids and
N-acylethanolamines are lipid mediators regulating a wide range of biological
functions including food intake. We investigated short-term effects of feeding
rats five different dietary fats (palm oil (PO), olive oil (OA), safflower oil
(LA), fish oil (FO) and arachidonic acid (AA)) on tissue levels of
2-arachidonoylglycerol, anandamide, oleoylethanolamide, palmitoylethanolamide,
stearoylethanolamide, linoleoylethanolamide, eicosapentaenoylethanolamide,
docosahexaenoylethanolamide and tissue fatty acid composition. The LA-diet
increased linoleoylethanolamide and linoleic acid in brain, jejunum and liver. The OA-diet increased brain
levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol)
without changing tissue fatty acid composition. The same diet increased
oleoylethanolamide in liver. All five dietary fats decreased
oleoylethanolamide in jejunum without changing levels of anandamide, suggesting
that dietary fat may have an orexigenic effect. The AA-diet increased
anandamide and 2-arachidonoylglycerol in jejunum without effect on liver. The
FO-diet decreased liver levels of all N-acylethanolamines (except
eicosapentaenoylethanolamide and docosahexaenoylethanolamide) with similar
changes in precursor lipids. The AA-diet and FO-diet had no effect on
N-acylethanolamines, endocannabinoids or precursor lipids in brain. All
N-acylethanolamines activated PPAR-alpha. In conclusion, short-term feeding of
diets resembling human diets (Mediterranean diet high in monounsaturated fat, diet high in saturated
fat, or diet high in polyunsaturated fat) can affect tissue levels of
endocannabinoids and N-acylethanolamines.
So it does appear that you should choose your fat
wisely. Olive oil (OA) seems the wise
choice.
PPARα and PEA
(Palmitoylethanolamide)
Here are two
papers that show that PPARα mediates the
anti-inflammatory effects of PEA:-
PEA attenuates
inflammation in wild-type mice but has no effect in mice deficient in PPARα. The natural PPARα agonist
oleoylethanolamide (OEA) and the synthetic PPARα agonists GW7647 and
Wy-14643 mimic these effects in a PPARα dependent manner.
These findings
indicate that PPARα mediates
the anti-inflammatory effects of PEA and suggest that this fatty-acid
ethanolamide may serve, like its analog OEA, as an endogenous ligand of PPARα.
Repeated treatments with PEA
reduced the presence of oedema and macrophage infiltrate, and a significant
higher myelin sheath, axonal diameter, and a number of fibers were observable.
In PPAR-α null mice PEA treatment failed to
induce pain relief as well as to rescue the peripheral nerve from inflammation
and structural derangement. These
results strongly suggest that PEA, via a PPAR-α-mediated
mechanism, can directly intervene in the nervous tissue alterations responsible
for pain, starting to prevent macrophage infiltration.
The present results demonstrate
the neuroprotective properties of PEA in a preclinical model of neuropathic
pain. Antihyperalgesic and neuroprotective properties are related to the
anti-inflammatory effect of PEA and its ability to prevent macrophage
infiltration in the nerve. PPAR-α stimulation is the common
pharmacodynamic code.
Ketogenic Diet & Autism
A pilot prospective follow-up
study of the role of the ketogenic diet was carried out on 30 children, aged
between 4 and 10 years, with autistic behavior. The diet was applied for 6
months, with continuous administration for 4 weeks, interrupted by 2-week diet-free
intervals. Seven patients could not tolerate the diet, whereas five other
patients adhered to the diet for 1 to 2 months and then discontinued it. Of the
remaining group who adhered to the diet, 18 of 30 children (60%), improvement
was recorded in several parameters and in accordance with the Childhood Autism
Rating Scale. Significant improvement (> 12 units of the Childhood Autism
Rating Scale) was recorded in two patients (pre-Scale: 35.00 +/- 1.41[mean +/-
SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88
+/- 3.14[mean +/- SD]), and minor improvement (2-8 units) in eight patients
(pre-Scale: 45.25 +/- 2.76 [mean +/- SD]). Although these data are very
preliminary, there is some evidence that the ketogenic diet may be used in
autistic behavior as an additional or alternative therapy.
Martha Herbert again:-
We report the
history of a child with autism and epilepsy who, after limited response to
other interventions following her regression into autism, was placed on a
gluten-free, casein-free diet, after which she showed marked improvement in
autistic and medical symptoms. Subsequently, following pubertal onset of
seizures and after failing to achieve full seizure control pharmacologically
she was advanced to a ketogenic diet that was customized to continue the
gluten-free, casein-free regimen. On this diet, while still continuing on
anticonvulsants, she showed significant improvement in seizure activity. This
gluten-free casein-free ketogenic diet used medium-chain triglycerides rather
than butter and cream as its primary source of fat. Medium-chain triglycerides
are known to be highly ketogenic, and this allowed the use of a lower ratio
(1.5:1) leaving more calories available for consumption of vegetables with
their associated health benefits. Secondary benefits included resolution of
morbid obesity and improvement of cognitive and behavioral features. Over the course of several years
following her initial diagnosis, the child’s Childhood Autism Rating Scale
score decreased from 49 to 17, representing a change from severe autism to
nonautistic, and her intelligence quotient increased 70 points. The
initial electroencephalogram after seizure onset showed lengthy 3 Hz spike-wave
activity; 14 months after the initiation of the diet the child was essentially
seizure free and the electroencephalogram showed only occasional 1-1.5 second
spike-wave activity without clinical accompaniments.
PEA clinical trials and dosage in
pain therapy
The
following paper gives a great deal of information about the clinical use of PEA:-
Conclusion
While many
kids with autism are given fish oil supplements, it is olive oil that I make a
point of using extensively. Today’s post
indicates that olive oil is a potent PPARα activator and so another reason
to use olive oil liberally.
PEA (Palmitoylethanolamide) itself almost
looks too good to be true. It does not
interact with other drugs and it seems to have no side effects. It has been trialed on many occasions, mainly
as a pain therapy, rather than in its anti-inflammatory capacity.
PEA also seems to have potential as an adjunct anti-cancer
therapy, rather like NAC also does.
It would be reasonable to expect a benefit from PEA in
autism, at least in certain subtypes – high histamine and seizures - and particularly where a sibling has
epilepsy, but no ASD.
