Showing posts with label Chez. Show all posts
Showing posts with label Chez. Show all posts

Friday, 9 December 2016

Glutamate Inhibitors to Treat Some Autism and ADHD

 A festive queue at the pharmacy for Glutamate Inhibitors

We have now established that much autism and indeed other disorders, from Down Syndrome to Schizophrenia, features a degree of excitatory/inhibitory (E/I) imbalance.

It is very likely that there are multiple underlying causes for this and so there may be multiple treatments.  We can even potentially use a treatment for one cause (ALS) to improve outcomes in others.  So we can (partially) solve a problem without fully understanding its origin, as frequently is the case in biology.

An E/I imbalance might cause anxiety in the adult with Asperger (treatable with Baclofen), contribute to MR/ID in the child with Down Syndrome and contribute to seizures and cognitive loss in someone with severe autism.

Very interestingly in the comments to a previous post, Agnieszka has pointed out why common penicillin type antibiotics (beta-lactams) improve many people’s autism.  This is very common observation and our other guest blogger Seth Bittker found the same in his son. Nat’s guest speaker at her autism conference also found this in his son.

The Glutamate Transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene.   It is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Glutamate is an excitatory neurotransmitter, so it encourages neurons to fire.

By upregulating the GLT1 transporter you increase the inactivation of glutamate and so shift the Excitatory/Inhibitory balance towards inhibitory.

Agnieszka highlighted this paper from Johns Hopkins:-

Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.

It actually gets more interesting and relevant to treatment.

Mutations in SLC1A2 which decrease expression of the GLT-1 protein are associated with amyotrophic lateral sclerosis (ALS). 

The drug riluzole approved for the treatment of ALS upregulates GLT-1.

This would suggest that Agnieszka, Seth and John Rodakis might want to pay a visit to the pharmacy and pick up some riluzole.  It is certainly worth investigating.

I did check and there is even a trial on Riluzole in autism and evidence of existing off-label use.  They have not of course made Agnieszka’s connection; they seem to be just trying it because nothing else seems to help. That really is trial and error and makes this blog look positively scientific by comparison.
Drug: Riluzole

50mg once daily (QD) for 12 weeks for participants 6-11 years old; 50mg twice daily (BID) for 12 weeks for participants 12-17 years old

A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223 is under development for the treatment of generalized anxiety disorder and mood disorders  by Biohaven Pharmaceuticals.

Anyway, are there any other ways to inhibit Glutamate?

Yes, our reader Valentine just stumbled on one, tizanidine, but there are at least two others. 

α2 adrenergic agonists

Three other known inhibitors of glutamate happen to be α2 adrenergic agonists

·        Clonidine

·        Guanfacine

·        Tizanidine

All three of the above are already used in ADHD and sometimes in autism, but not to reduce glutamate.

I wrote a post about Clonidine use in autism a long time ago.

Guanfacine is an ADHD drug known to inhibit glutamate release.

At five sites, children with ASD and moderate to severe hyperactivity were either given guanfacine or a placebo tablet for eight weeks, in a randomized and double-blind clinical trial. The research team collected information from parents and measured each child’s overall response. After eight weeks of treatment, extended release guanfacine was superior to placebo for decreasing hyperactivity and impulsiveness.

Our reader Valentina seems to have stumbled upon tizanidine, but finds it helpful for her son. Tizanidine is a α2 adrenergic agonists but also inhibits glutamate.  It is one of the drugs used off-label by Dr Chez in ADHD and autism


The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.


Ideally you would have a comparison of the four drugs:

·        Riluzole

·        Tizanidine

·        Clonidine

·        Guanfacine

We know clonidine is not an autism wonder drug, but then what is?

I think Riluzole is likely to be a good one, but very likely what works best will vary from person to person.

Perhaps a positive response to beta-lactam (penicillin) antibiotics is a biomarker for people who will respond to Riluzole? It should be.

Tuesday, 29 July 2014

Steroids for Regressive Autism

As we have seen at various points in this blog, there is mounting evidence to support the use of steroids in autism, particularly in regressive autism.

Since long-term steroid use has side effects, there have been no large long-term trials.  There is plenty of anecdotal evidence, particularly from the US.  We saw a paper on Immunomodulatory Therapy, by Michael Chez, which discussed the benefits of Prednisone, a very cheap oral steroid.

In the days before inhalers for asthma, it was low dose oral prednisone that kept many sufferers from an early death.  It did result in reduced height, but this is probably a price worth paying to stay alive.

A paper was recently published by specialists at Harvard Medical School on the subject of steroids and regressive autism.

It pretty much concludes the same as Chez and others have been saying for many years; corticosteroids can have a profound effect on some types of autism.  It remains unlikely that there will ever be large scale trials, due to the scaremongering about side effects.  Much is known about how to minimize the side effects of steroids, for example tapering and pulse dosing.

Here are some key points from the paper:-

·        Up to a third of children with Autism Spectrum Disorder (ASD) manifest regressive autism (R-ASD).They show normal early development followed by loss of language and social skills. Absent evidence-based therapies, anecdotal evidence suggests improvement following use of corticosteroids
·        Twenty steroid-treated R-ASD (STAR) and 24 not-treated ASD patients (NSA), aged 3 - 5 years, were retrospectively identified from a large database.
·        Star group subjects’ language ratings were significantly improved and more STAR than NSA group subjects showed significant language improvement. Most STAR group children showed significant behavioral improvement after treatment. STAR group language and behavior improvement was retained one year after treatment. Groups did not differ in terms of minor EEG abnormalities. Steroid treatment produced no lasting morbidity
·        Steroid treatment was associated with a significantly increased FMAER response magnitude, reduction of FMAER response distortion, and improvement in language and behavior scores. This was not observed in the non-treated group. These pilot findings warrant a prospective randomized validation trial of steroid treatment for R-ASD utilizing FMAER, EEG, and standardized ASD, language and behavior measures, and a longer follow-up period.
·        Referring physicians often enquire about the utility of adrenal corticosteroids or glucocorticoids to treat patients with R-ASD

Prednisone is already a treatment used in PANS, PANDAS and Landau-kleffner syndrome, which all have autism-like symptoms.


Slightly off-topic but, the following is relevant.  

There was a recent documentary by the BBC about US-style DAN autism therapies now being sold to parents in the United Kingdom.  The UK has a government funded institute (NICE) that publishes lengthy advice to doctors as to what drugs to prescribe for almost all conditions, including autism. UK doctors will get into trouble if they do not follow NICE guidelines.

Commenting for the BBC, on the DAN-type treatments, Francesca Happe, a professor of cognitive neuroscience at King's College London and apparently one of the world's leading researchers into autism, said practitioners who "peddled" treatments without proof were "wicked".

But how much proof do you need?  And who is to say which published researcher is serious and which is a charlatan.  The lay autism parent might (falsely) assume that if a researcher is publishing papers, they must be serious and the conclusions reliable.  The reality is that some of the papers are indeed flawed and the conclusions are nonsense.  That is why I keep a list of the researchers who I believe in.

At the extreme are bodies like the UK’s NICE, who conclude that absolutely none of the hundreds/thousands of drugs/supplements proposed for treating core-autism should be used.

The short version of the NICE clinical guidelines is below.  The much longer version reviews in detail many of the papers I have reviewed in this blog, but comes to a very different conclusion.

I read the same papers as NICE and concluded something entirely different.  I found several drugs that do indeed work.  The difference is that my standard of proof is lower than that of NICE and professor of cognitive neuroscience at King's College London.

The DAN/TACA/MAPS/ARI doctors from the US are also hopefully read all these papers, but they come up with ideas of the sort that do fall into the “wicked “category mentioned above.  

Autism parents are not surprising bewildered.  It is the parent that ends up deciding where to draw the line between what treatment is genuine and what is fantasy, perhaps like this one.


Yet again, we have a therapy based on solid science that is in use by a very small number of serious mainstream doctors.  It has not crossed into general use due to a lack of large scale trials.

As a result, medical science continues to tell families that there are no drug therapies for core autism, except some anti-psychotics, anti-depressants and anticonvulsants most of which have serious side-effects and/or cause dependence.

In the case of prednisone, this is a cheap generic drug that does have side effect with prolonged use.  Severe regressive autism can also have side-effects, like complete loss of speech and cognitive impairment.

The answer might be parents signing a waiver to get open access to drugs that have been used successfully in experimental use for autism, without the doctor worrying about losing his license, or being blamed for any side effects.

Friday, 25 July 2014

Carnosine for Autism – an Alternative to N-Acetylcysteine (NAC)? or is it Complementary?

Several people have mentioned to me a supplement called L-Carnosine, so I thought it was worthy of its own post.

The first thing to note is lots of supplements have very similar names and indeed two entirely different substances are abbreviated to NAC.

·        Carnosine
·        Carnitine
·        L-Carnosine
·        L-Carnitine
·        N-Acetylcysteine    (abbreviated to “NAC”)
·        N-Acetylcarnosine  (also abbreviated to “NAC”)

In this blog, and in most literature on autism, NAC refers to N-Acetylcysteine.

This post is about Carnosine and L-Carnosine, but there is also research on the use of Carnitine and L-Carnitine regarding autism and Retts syndrome.  So double check what is on the label, if you do indeed order some.

Vladimir Gulevich, Carnosine (and Carnitine)

Vladimir Gulevich  received the degree of doctor of medicine in 1896 from the department of medicine of Moscow State University. From 1900, he rejoined the Moscow State University where he was rector for a brief period of time in 1919. He was a full member of the USSR Academy of Sciences since 1929.

Gulevich discovered both Carnosine and Carnitine in his work in Moscow.  Even today his university is a centre of research for both these substances.

Carnitine and carnosine are composed of the root word carn, meaning flesh, alluding to its prevalence in animal protein. A vegetarian (especially vegan) diet is deficient in adequate carnosine, compared to levels found in a standard diet.

Researchers in Britain, South Korea, Russia and other countries have shown that carnosine has a number of antioxidant properties that may be beneficial.

Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress.

Carnosine can chelate divalent metal ions.  DAN Doctors probably do not know what divalent means, but in Hg2+ the “2” means divalent and Hg means mercury.

Carnosine was found to inhibit diabetic nephropathy.

Carnosine-containing products are also used in topical preparations to reduce wrinkles on the skin.

Some studies have detected beneficial effects of N-acetylcarnosine in preventing and treating cataracts of the eyes.

Carnosine and Autism

Small studies, including this one by Michael Chez, have shown the benefit of L-carnosine in autism.  By the way, Chez seems to be one of the handful of genuinely knowledgeable autism clinicians anywhere on the planet.


L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.

As Dr Chez points out, nobody is 100% certain why it is of benefit.  It could just be the anti-oxidant properties of carnosine or it could be something related to the interaction between carnosine and GABA in the brain.  GABA is an important neurotransmitter in the brain.

Other GABA related drugs show a positive effect in types of autism.  These include Baclofen, Arbaclofen, Bumetanide, Clonazepam and even Valproic acid (VPA).  The underlying mechanisms do differ, but all relate, in one way or the other, to GABA.

The Carnosine dosage used by Dr Chez was 800mg per day.

The body deploys a range of enzymes, called carnosinases, to break down carnosine.  In order to maximize the effect, and out-smart the  carnosinases, it might be wise to split the dose into two per day.

In a perfect world it might be simpler to inhibit the carnosinases and just rely on the carnosine from meat in the diet.

You cannot patent naturally occurring substances, so nobody can patent carnosine and no drug firm will therefore research it.  A carnosinase inhibitor could be patented and therefore could be made into a drug.

Carnosine and GABA

It looks like Moscow State University is still the centre of knowledge for Carnosine and Alexander A. Boldyrev recently published a book called:-

Book Description:

The main aim of this new book is to summarize the knowledge on the metabolic transformation of carnosine in excitable tissues of animals and human beings and to analyze the nature of its biological activity. At the beginning of monograph, the short history of the problem is stated. Distribution of carnosine in tissues, its appearance in ontogeny of vertebrates and correlation between carnosine content and functional activity of tissues are discussed. Chemical properties of carnosine and its natural derivatives and their ability to bind heavy metals and protons in water solution are documented. Special attention is paid to free radical quenching ability and to anti-glycating action. Biological activity of carnosine and carnosine containing compounds was tested using biological models of several levels of complexity, starting from individual enzymes and acellular mixtures and finishing to living cells and survival animals. Effects of carnosine on the whole animals under ischemic, hypoxic and other extreme conditions are described. In conclusion, the ability of carnosine to protect brain and muscular tissues from oxidative injury during exhausting exercise, extreme loading or neurodegenerative diseases is demonstrated. Based on these properties, carnosine is postulated to be a potent protector of human beings from oxidative stress.

You can preview much of the book on Google Books

We know from many autism researchers that oxidative stress is a feature of many people’s autism.  Anything that reduces this stress should have a positive effect on behaviour.

Common antioxidants used in autism include:-

·        N-Acetlycysteine (NAC)
·        Alpha Lipoic Acid (ALA)
·        All the many “chelating” substances used by DAN Doctors

Carnosine may be just an alternative anti-oxidant.

However, when you look through Boldyrev’s book, it does look possible that the chemical relationship between GABA and Carnosine many also play a role.


People currently taking Carnosine for Autism might well want to try N-Acetlycysteine (NAC) and see if they notice an additional benefit.  Conversely, the current NAC converts, like my son Monty, aged 11 with ASD, may well want to give Carnosine a try and see what happens.

One blog reader with Asperger’s finds Baclofen highly beneficial; he might as well give Carnosine a try, based on the GABA relationship.

Current research indicates 2,400 mg of NAC and 800 mg of Carnosine. 

It would be nice if one day somebody would do a controlled trial of NAC vs Carnosine vs Carnosine+NAC;  but don’t hold your breath.

Some people with diabetes are already taking ALA (Alpha lipoic acid) or Thioctacid for neuropathy, but find it also increases insulin sensitivity; this means they need less insulin.  They might well find both NAC and Carnosine will further increase insulin sensitivity.  Generally speaking it seems that low insulin sensitivity is bad and high insulin sensitivity is good; but I am no expert on diabetes.

In some counties Carnosine is not available, but you simply can buy it online on Amazon, ebay or many other sites. 

Thursday, 20 March 2014

Dr Chez’s Trial of Lenalidomide, a TNF- α and IL-6 Inhibitor in Autism


An interesting trial of a TNF- α and IL-6 inhibitor in autism has been brought to my attention.  It was by Michael Chez, the neurologist from Sacramento, who has made several appearances on this blog.
By coincidence, a copy of his book arrived this week.  The book is called “Autism and its Medical Management”, Chez is one of the few mainstream doctors who does try and treat autism.  The book is rational, readable and in no way radical, so you could show it to your family doctor without upsetting him/her.  Chez does particularly focus on distinguishing regressive from non-regressive autism, as do I. His view is that it is regressive autism, even if it was regression from slightly abnormal.  The important part is that some learned skills, like language, were lost sometime after 12 months of age.  He believes that regressive autism has a different basis to non-regressive autism; he has his own ideas about this, but he admits there is no concrete proof.

The book is a few years old and Chez has published much work in the intervening few years.    
The paper I was referred to is:-

Lenalidomide, an analogue of thalidomide, has the potential to invoke significant changes in TNF-α and other immunomodulatory cytokines.  If thalidomide sounds familiar, it is the drug from the 1950s, that turned out to be very unsafe for use in pregnant women and around the world 10,000 babies were born with malformation of the limbs.

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past 10 years. There are multiple mechanisms of action.  It is extremely expensive, according to NICE:-

“Lenalidomide 25 mg capsules cost £4368 per 21 capsules (excluding VAT; ‘British national formulary’ [BNF] edition 55). Dosage is continued or modified based upon clinical and laboratory findings. For example, if lenalidomide is continued for ten 28-day cycles without dose reduction, the cost would be £43,680.”
Dr Chez does not mention the cost of Lenalidomide, but he uses a tiny dose of 2.5 mg; This would cost £20, or $30, a day.  This might also explain the small number (7) of participants in the trial.
“2.2. Drug and Dosing. Lenalidomide 2.5mgs was given daily
for 12 weeks. This low dose was selected to minimize the risk
of adverse effects. In addition, because this was a pilot study,
the goal was to test the lowest dose that could potentially lead to improvements.”
The drug did reduce TNF-α levels and there were some behavioral improvements, but nothing dramatic.  Perhaps a higher dosage would have had a greater effect?
There were only seven participants and the data on the seven is not complete; also the dose of Lenalidomide was very low.  I think it is really only fair to conclude that the trial is interesting but that a much cheaper drug would need to be found and tested on a much larger number of participants.

“Despite the limitations, to our knowledge, this open-label study represents the first attempt to treat autism by specifically targeting elevated innate inflammatory cytokine levels. Safety monitoring and pharmacokinetic data were successfully completed during this pilot study and exploratory observations of clinical and cytokine changes suggest a trend towards improvement. Correlating treatment outcomes with cytokine level changes may be a target in future autism spectrum treatment, especially in those with known maternal or postnatal immunological risk factors. Larger blinded and placebo-controlled studies assessing cytokine measurement and cytokine-targeted treatment in autism patients with TNF-α or other inflammatory cytokine elevation are warranted.”

To his credit, unlike the researchers in Athens who trialed Neuroprotek in a recent post, Chez went about his pilot study in a scientific manner and collected both the biological and the behavioral data.  In other words, he measured the before and after levels of the inflammatory cytokines and the before and after behavioral rating scales.  Well done Dr Chez.

Wednesday, 12 March 2014

Single Dose of IL-6 Antibodies or TNF-ᾳ Inhibitor as Potential Disease-Changing Autism Therapies

We have noted in earlier posts that autism is a dynamic encephalopathy and this may help explain why a therapy that works in a child aged 10, may be of little help to another child aged 3.  Not only are there many sub-types of autism, but each sub-type is evolving, as the child matures.

None of the autism drug therapies I have implemented have permanent disease changing effects, they all seem to work, but the effect is lost once you stop taking them.  Today’s post is about drugs that you take just once.  For a parent trying to find a drug that works in the sub-type affecting their child, this has a big advantage.  No need to keep trying for months to see if the drug has any effect.
Perhaps the most important time to intervene with drug therapy is as soon as possible after the diagnosis; but with what?
In an earlier post on trying to get a non-verbal child to talk, I suggested the use of corticosteroids to arrest on-going neuroinflammation.  Drugs like prednisone are potent, but they these have nasty side-effects if used long term. In that post, Dr Michael Chez, an eminent neurologist from Sacramento, was upbeat on their potential as immunomodulators.  We will refer back to him in this post as well.
In this post I will give more background about the role of a cytokine called Interleukin 6, or just IL-6, in autism.  You will see how science can both create a mouse with autism using IL-6 and reverse it again using IL-6 antibodies.
We will also look at another cytokine called   TNF-ᾳ and see how a single dose of a TNF-ᾳ inhibitor can improve chronic neurological dysfunction following a stroke, TBI and indeed autism.  It is effective even a decade after the original traumatic event.
Both the IL-6 and TNF-ᾳ drugs are developed for arthritis and these drugs cost tens of thousands of dollars a year, but in the case of neurological conditions they may have a disease-changing effect when used just once. Remarkably, both drugs are already approved for long term use in very young children with Juvenile Idiopathic Arthritis.

Why am I interested in Cytokine inhibition?
My very first attempt to reduce neuroinflammation in Monty, aged 10 with ASD, was a very surprising, but resounding success.  That followed my research into cytokine storms and statins.  I know it works, because when I stop the statin, the very same behavioural improvement is lost in a day or so.
Are there randomized trials of atorvastatin in autism? Sadly, not; but it is a safe intervention that works in my mouse model.
Are there further potential benefits from such therapy? Quite possibly, but higher doses of statins have side effects.
We saw in recent posts that PEA, quercetin and luteolin also inhibit pro-inflammatory cytokines.  Is there a potential disease-changing therapy?  We will only find one, if we look.

The Cytokine IL-6 and Autism
Thanks to Dr Wei, we have some excellent research linking specifically the cytokine IL-6 to autism.  He suggests that elevated levels of IL-6 may cause much of the damage in autism and he went as far as to prove it in a mouse model.

A single injection of IL-6 into a pregnant mouse, produced a mouse pup with social deficits.  When the mother received a dose of IL-6 antibodies the resulting mouse pup has normal behaviour.  Humans are not mice, but we do already know from Ashwood and others that people with ASD have elevated levels of IL-6 and in particular those people with regressive autism.  
Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. Emerging evidence suggests that aberrant neuroimmune responses may contribute to phenotypic deficits and could be appropriate targets for pharmacologic intervention. Interleukin (IL)-6, one of the most important neuroimmune factors, has been shown to be involved in physiological brain development and in several neurological disorders. For instance, findings from postmortem and animal studies suggest that brain IL-6 is an important mediator of autism-like behaviors. In this review, a possible pathological mechanism behind autism is proposed, which suggests that IL-6 elevation in the brain, caused by the activated glia and/or maternal immune activation, could be an important inflammatory cytokine response involved in the mediation of autism-like behaviors through impairments of neuroanatomical structures and neuronal plasticity. Further studies to investigate whether IL-6 could be used for therapeutic interventions in autism would be of great significance

Background: Although the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS) may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS. 

Methods: Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively.

Results: In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses.

Conclusions: Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of  excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.  

Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors.
Abnormal immune responses have been reported to be associated with autism. A number of studies showed that cytokines were increased in the blood, brain, and cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has been a consistent finding. However, the mechanisms by which IL-6 may be involved in the pathogenesis of autism are not well understood. Here we show that mice with elevated IL-6 in the brain display many autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety traits and habituations, as well as decreased social interactions. IL-6 elevation caused alterations in excitatory and inhibitory synaptic formations and disrupted the balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also resulted in an abnormal change in the shape, length and distributing pattern of dendritic spines. These findings suggest that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity. 


Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.

Effects of exogenous cytokines

Our pilot studies indicated that maternal administration of IL-6, but not IL-1α, tumor necrosis factor α (TNFα), or IFNγ, causes PPI deficits in the adult offspring. PPI is the inhibition of a startle response when the startling stimulus is immediately preceded by a smaller, nonstartling stimulus of the same modality and is a measure of sensory-motor gating, attention, and distractibility. PPI deficits are observed in several mental disorders, including schizophrenia and autism. Furthermore, PPI deficits in the offspring elicited by maternal influenza infection respond to antipsychotic and psychomimetic drugs, and the PPI deficit resulting from poly(I:C) MIA is present in adult but not juvenile rats, mimicking the adult onset of schizophrenia. The changes seen in this very relevant behavior prompted further study of the effects of maternal IL-6 administration

Thus, a single injection of IL-6 on E12.5 causes deficits in two relevant behaviors (LI and PPI) in the adult offspring.
Abnormal behavior in MIA offspring is prevented by maternal treatment with anti-IL-6 antibody
f, In the social interaction test, control mice show a strong preference for the social chamber [defined as (percentage of time in social chamber) – (percentage of time in opposite chamber)], whereas the offspring of poly(I:C)-treated mice show no such preference. Again, the deficit is corrected by maternal administration of IL-6 antibody

Tocilizumab / Actemra
Wei has made a pretty solid case that IL-6 is implicated in autism and that IL-6 inhibition could be a very interesting therapy.  While we have a range of interventions that can do just that, the ultimate therapy would be IL-6 antibodies.
This therapy does actually exist as a recent option in treating arthritis. Tocilizumab, brand name Actemra, is an immunosuppressive drug made of humanized monoclonal antibodies  against the interleukin-6 receptor (IL-6R)  In 2013 Actemra was approved by the FDA for children as young as 2 years old, as an ongoing treatment for arthritis.

This drug is frighteningly expensive and in arthritis you need to keep taking it regularly.
Now let us look at another related very expensive drug. Etanercept (trade name Enbrel).  Enbrel is another immunosuppressive drug for arthritis , but this time it is not inhibiting IL-6 but rather tumor necrosis factor (TNF).
This drug also treats a condition called psoriasis.  There is a case of a 53 year old Italian lady only partially verbal and by the sound of it, autistic, living with her mother.  She had her psoriasis treated with Enbrel and suddenly she became social and her speech improved.  Now an example of one is definitely interesting, but it does not prove anything.
But, remember Dr Chez from Sacramento?  Tucked away in his excellent paper of immunomodulation in autism.

"A single case of repetitive regression, with bouts of inflammatory colitis in an 8-year-old with regressive autism after age 3, has shown elevated serum TN alpha levels and rapid colitis, as well as behavioral and language improvements after injections of etanercept (unpublished data, personal communication Y. Davies and M. Chez 2008)."

At the time, I did not pay much attention since who can afford an ongoing therapy costing tens of thousands of dollars a year?
But, there is more.
In the US, a controversial doctor has been treating various chronic neurological dysfunctions with single dose etanercept.  He was criticized both for his marketing and the lack of published research to back up his claims.  To his credit, he is now publishing his work and has patented his therapy.

Here is a press article.

Here is an abstract of the study:-

Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept.



Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier.


The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI.


After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.


The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced.


Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.


Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.

Now I am fully aware that author, Dr Tobinick,  has got into trouble with the Medical Board of California for his marketing approach.  Here is a link for those interested.  This does not mean his off-label use of etanercept is without merit.
Etanercept (trade name Enbrel) is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.
Other comorbidities

You might view arthritis and psoriasis as as being related rather than being comorbid with autism.  Are there other comorbid conditions where anti-cytokine therapy is used?

One example is Irritable Bowel Disease (IBD), where several anti-TNF-alpha drugs have been shown to be effective and are widely prescribed.  IBD includes ulcerative colitis (UC) and the more severe Crohn’s disease.  UC does appear to be comorbid with autism and indeed UC itself does seem to be associated with mild autistic behaviours.  You will find adults with UC debating whether or not they have Asperger’s.

Here is a short video on anti-TNF therapy in IBD.

The complete set of video on IBD can be found here:-

For those scientists among you here is a full paper on this subject:- 
Pro-Inflammatory Cytokines in the Pathogenesis of IBD


I am surprised that nobody has sought to do even a very small trial of Etanercept/Enbrel or Tocilizumab/Actemra in autism. These potent immunomodulatory drugs can have side effects with long term use, but the case reports suggest that a single dose can be disease changing in neurological conditions, like autism.
In all likelihood only a single dose would be needed, so you really would not need the usual years of delay to complete a trial.  There is a lot of interest in GH and IGF-1 therapy in autism, which both require ongoing injections. To trial Etanercept and Tocilizumab would be so easy, in comparison.
Because the mechanism of action is fully understood, and IL-6 and TNF-ᾳ are easy to measure, it would later be possible to identify the people most likely to benefit from the cytokine lowering therapy.  Quite possibly it would be people with regressive autism who would benefit most, since they have the highest level of inflammatory markers, as highlighted by Ashwood.
If indeed the therapy worked, it is not going to be cheap; but at least it would be a one-off cost of $1,000 to $2,000, rather than a monthly cost as in severe arthritis.
I think our new friend Dr Wei would favour Tocilizumab/Actemra. If you live in California, Dr Tobinick would be the one to ask about Etanercept/Enbrel, but it won’t be cheap.

If medicine was a true science, we would have longitudinal autism studies that showed the level of inflammatory cytokines over time.  Then we would be able to say, for example, when regression occurs there is acute neuroinflammation with a spike in IL-6,TNF-ᾳ and other cytokines. 
Perhaps this inflammation does some long term damage that might be halted with immediate immunomodulatory therapy.  If the data did show this, we could look for correlations between later behavioral improvement and falling level in inflammatory cytokines. 
In children with regressive autism and who do not improve much, do the inflammatory cytokines stay at high levels?  Are the behavioral problems caused by the current level of inflammatory cytokines, or is the problem caused by the long term damage the cytokines already caused?  With data, all these questions could be answered.  Without data it is just conjecture.
All you need to do this research are regular blood samples.  The tests themselves are cheap.  Then you could compare cheap immunomodulatory therapy using steroids versus the expensive arthritis injections used one-off.