Showing posts with label GH. Show all posts
Showing posts with label GH. Show all posts

Thursday 13 March 2014

IL-6 Disrupts the GH→IGF-1 Axis in Autism

Regular readers of this blog will see that there is an underlying logic behind recent posts.  We know levels of the cytokine IL-6 are raised in autism and we know that high levels of IL-6 in mice produces a baby with autism and we know this can be reversed by giving IL-6 antibodies to the mother, prior to birth.
We also know from numerous previous posts that growth hormone (GH) and the growth factor IGF-1 are implicated in autism.  Both GH and IGF-1 are used in clinical trials for autism.

Today’s post draws all this together.  It turns out that IL-6 disrupts the GH-IGF-1 axis.  The hormone GH is supposed to control the release of IGF-1; so a little more GH should produce a little more IGF-1.  The problem is that the cytokine IL-6 disrupts this relationship.  In the presence of elevated amounts of IL-6, which is characteristic of autism, and regressive autism in particular, GH does not produce the expected increase in IGF-1; IGF-1 levels are actually reduced.
This is very important.
A great deal of money is being spent researching and developing IGF-1 based therapies for autism and Retts syndrome.  Perhaps a much better strategy would be to clear the disruption from the GH-IGF-1 axis, so that IGF-1 levels could be restored naturally.  This means reducing IL-6 levels and IL-6 mediated disruption. We already know how to do this, from previous posts.
Now for some supporting evidence:-
In the following study, IL-6 was given to healthy volunteers and the over the next 8 hours their levels of GH and IGF-1 were measured.

The study confirmed earlier observations that IL-6 infusion leads to increased circulating GH. Despite the increase in GH levels, the study demonstrated an IL-6 infusion-associated reduction in IGF-I. 


Coming back to mice being given IL-6 to produce autistic pups, Autism Speaks funded a very thorough post-doctoral study at Caltech that focused on understanding this very issue (in mice at least).  The study aimed to find out how IL-6 ends up causing autism.  The conclusion is very interesting and again comes back to endocrine changes and the disrupted GH-IGF-1 axis.

I rest my case. 

"Activation of the maternal immune system in rodent models sets in motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between mother and fetus and as a principal modulator of fetal development. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway specifically in the  pongiotrophoblast layer of the placenta, which results in expression of acute phase genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor (GHIGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K (PLP-K) expression as well as MIA-related alterations in other placental endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta represent an indirect mechanism by which MIA can alter fetal development. 

Furthermore, we find an IL-6-dependent dysregulation of the GH-IGF axis in MIA placentas, characterized by decreased levels of GH and IGFI mRNA, with corresponding decreases in placental IGFI and IGFBP3 protein. The actions of GH are achieved through the stimulation of IGFI production in target tissues. In addition, GH regulates the activity of IGFI by altering the production of either facilitatory or inhibitory binding proteins, including the IGFI stabilizing protein, IGFBP3. This suggests that the decreased GH levels seen in MIA placentas leads to the observed downstream suppression of IGFBP3 and IGFI production. It is believed that IGFs in the maternal circulation do not enter the placenta, and therefore IGFs in the placenta are derived from the placental compartment itself We demonstrate that the changes in IGFI and IGFBP3 expression are mediated by IL-6. However, it is unclear whether decreases in placental GH and subsequent effects on IGF production are downstream of IL-6-specific STAT3 activation. IL-6 does modulate IGFI and IGFBPs in several tissues, including placenta and cord blood. Pro-inflammatory cytokines, including IL-6, decrease circulating and tissue concentrations of GH and IGFI. We observe that IL-6- mediated STAT3 activation is associated with the expected IL-6- mediated increase in SOCS3 expression, along with other acute phase genes. Factors like SOCS play an important role in the down-regulation of GH and GH signaling. Importantly, it is reported that IL-6 inhibits hepatic GH signaling through up-regulation of SOCS3. As such, it is possible that, in MIA placentas, maternal IL-6-induced STAT3 activation and downstream sequelae lead to suppression of placental GH levels, disruption of IGFI production and further consequences on maternal physiology, placental function and fetal development. Altered placental physiology and release of deleterious mediators to the fetus are important risk factors for the pathogenesis of neurodevelopmental disorders. Placental IGFI in particular regulates trophoblast function , nutrient partitioning and placental efficiency. Moreover, altered IGFI levels are associated with intrauterine growth restriction (IUGR) and abnormal development. Animal models of IUGR and intrauterine infection, where the immune insult is confined to the uteroplacental compartment, highlight the key role of placental inflammation in perinatal brain damage, involving altered cortical astrocyte development, white-matter damage, microglial activation, cell death and reduced effectiveness of the fetal blood–brain barrier. In addition, adult pathophysiology is subject to feto-placental ‘‘programming’’, wherein molecular changes that occur prenatally reflect permanent changes that persist throughout postnatal life. Interestingly, placental responses to maternal insults can potentiate sexually dimorphic effects on fetal development. Obstetric complications are linked to schizophrenia risk and to the treatment responses of schizophrenic individuals. Notably, a greater occurrence of placental trophoblast inclusions was observed in placental tissue from children who develop autism spectrum disorder (ASD) compared to non-ASD controls. Chorioamnionitis and other obstetric complications are significantly associated with socialization and communication deficitis in autistic infants. The characterization of placental pathophysiology and obstetric outcome in ASD and schizophrenic individuals will be useful for the identification of molecular mechanisms that underlie these disorders and for potential biomarkers for early risk diagnosis. In addition to the observed effects of IL-6 on placental physiology and its downstream effects on fetal brain development and postnatal growth, direct effects of IL-6 on the fetal brain are also likely. Maternal IL-6 can potentially cross the placenta and enter the fetus after MIA. Furthermore, IL-6 mRNA and protein are elevated and STAT3 is phosphorylated in the fetal brain itself following MIA, raising the obvious possibility that IL-6 acts directly on the developing brain to influence astrogliosis, neurogenesis, microglial activation and/or synaptic pruning. However, recall that the identification of IL-6 as a critical mediator of MIA is based on maternal co-injection of poly(I:C) and anti-IL-6 blocking antibody, in addition to experiments inducing MIA in IL-6 KO animals. As such, in considering which pool(s) of IL-6 (e.g. maternal, placental, fetal brain, fetal periphery) is the ‘‘critical mediator’’, it will be important to understand the potential interaction between maternal IL-6 and fetal brain IL-6 expression. While we believe that the endocrine changes triggered by maternal-IL-6 signaling in the placenta reported here are important for fetal growth, it will be crucial to assess the potential impact of these placental changes on offspring behavior and neuropathology. We are currently exploring the effects of MIA in targeted IL-6Ra KOs in order to tie tissue- and cell-specific IL-6 activity to the manifestation of schizophrenia- and autism-related endophenotypes."

Saturday 1 March 2014

PPARα (Peroxisome proliferator-activated receptor alpha) - and why PEA might be an alternative to the Ketogenic Diet in Epilepsy and Potentially useful in Autism

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.



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:-

Influence of dietary fatty acids on endocannabinoid andN-acylethanolamine levels in rat brain, liver and small intestine.



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:-

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.