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Showing posts with label IBD. Show all posts
Showing posts with label IBD. Show all posts

Monday, 23 February 2015

Nystatin in autism - a potent Potassium Channel Kv1.3 blocker (anti-inflammatory) or an antifungal/candida treatment?


Today’s post will go against some people’s understanding of autism and inflammatory bowel disease.

Just as there is a belief that heavy metals are a problem in autism there is another is another belief that candida is involved in autism and indeed inflammatory bowel disease (IBD).  Various types of IBD are highly comorbid with autism, but most people with IBD do not have autism.
The most common treatment for candida is an antifungal medicine called nystatin.  This drug is a cheap and widely available.

But nystatin has another property, it is a highly effective blocker of the potassium channel Kv1.3.

Regular readers will recall that this ion channel is key mediator in the inflammatory process, it is a target in many inflammatory conditions such as IBD and indeed autism.  Those little helminths (TSO) parasites that are being researched for both autism and IBD were found to reduce inflammation by releasing their own Kv1.3 blocker which stops the host (human or animal) from rejecting them.






Abstract: Background: Autism children were reported to have gastrointestinal problems that are more frequent and more severe than in children from the general population. Although many studies demonstrate that GI symptoms are common in autism, the exact percentage suffering from gastrointestinal (GI) problems is not well known, but there is a general consensus that GI problems are common in autism. The observation that antifungal medications improve the behavior of autism children, encourage us to investigate their intestinal colonization with yeasts. Aim of the work: The purpose of this work was to investigate the intestinal colonization with yeasts in autistic patients and to assess the role of yeast as a risk factor to cause autism behavior. Patients and methods: The study included 83 cases diagnosed as autistic children referred from the neuro-pediatric clinic and 25 normal children as a control group. All children under the study came to Phoniatric clinic, during the period from 2010 to 2012, complaining of delayed language development with autistic features. Children in this study were classified into 2 groups; control and study groups. All children were subjected to interview, E.N.T examination, language assessment, Childhood Autistic Rating Score (CARS), stool culture for Candida albicans, complete audiological and psychometric evaluation. Results: There was significant relation between the autistic children and heavy growth of Candida albicans in stool culture. Conclusion: The high rate of Candida albicans intestinal infection in autistic children may be a part of syndrome related to immune system disorders in these patients.





Conclusion: Candida albicans infection may be a part of syndrome related to the immune system and depends on genetic basis of autism, or Candida albicans may be etiological factor lead to excessive ammonia in gut which is responsible of autistic behavior in children. More researches are needed to clarify the exact mechanism by which Candida albicans affects autistic children.


  
In another study the results were not so clear:-



This study was done by James Adams (of the Autism Research Institute, former home of DAN).  According to Wikipedia, Adams' research has been described as "a laundry list of autism woo"; I think he is well intentioned.

You would have expected him to find Candida, but he did not. 

Note that they did not find any parasites either, although they did give up testing after the first 20 results were negative (not very scientific, I think).  Regular readers will know that some “holistic doctors” insist that parasites are the cause of autism.
  

Yeast

The presence of yeast was determined by both culture and by microscopic observation. Yeast was only rarely observed by culture in the autism or typical groups, and the difference between the two groups was not significant, as shown in Table Table5.5. Yeast was more commonly observed microscopically, but again the difference between the two groups was not significant.

Parasitology

The parasitology test was used on the first 20 autism samples only, which were all negative. It was then decided to do no additional testing on other samples

  
The finding that yeast levels were similar in both the autistic and control group is interesting, as there has been a great deal of speculation that yeast infections are a major problem in autism. Our data indicates that yeast is present at normal levels in the stool of this group of children with autism. A study by Horvath and Perman [21] reported that 43% of children with autism undergoing endoscopies had a positive fungal culture for yeast in their duodenal juice, vs. 23% of age-matched controls with other gastrointestinal problems requiring endoscopies. Since their study involved children with severe enough symptoms to warrant endoscopies, the greater symptom severity may explain some of the difference with our study. Since the survey by the Autism Research Institute of over 25,000 parents' reports that parents find antifungals to be one of the most effective medications for improving behavior [44], our findings are puzzling. It is possible that children with autism are more sensitive to even a normal level of yeast. Also, it is possible that antifungals have other effects, such as reducing inflammation.

  
Which Study to believe?

I have to say that I give more credence to the first study, which is from Egypt.

I think that autism in Egypt is likely to be the “real deal”.  People with severe autism will likely have associated auto-immune/inflammatory conditions and this will include abnormal GI conditions.

Also, the more severe the autism, the more restrictive the diet is likely to be, which will affect what grows inside the intestines.   

   
Ion Channels and Channelopathies

Ion channels are complex, but fortunately there are not that many of them, unlike genes.

A good source of information is provided by École polytechnique fédérale de Lausanne, on the banks of lake Geneva.  On their Channelpedia site you can see a nice entry on the potassium channel Kv1.3.  It may all look rather too complicated, but there under the Scorpion toxin, is a very common drug, Nystatin.



Interactions


PAP-1

MbCD and MbCD/C

Zn

Leukocyte Subunits effect Kv1.3

Cluster at C-terminus

Kv1.3 associates with Kv1.5

Kv1.3 forms heteromeric channels

Scorpion toxin ADWX-1 is a pore blocker of Kv1.3 channel without affecting its kinetics

Nystatin

The concentrations for nystatin and its structural analog, amphotericin B, required to produce half maximal inhibition (IC50) of the current were estimated to be about 3 and 60 microM, respectively. The effects of nystatin on the amplitude and inactivation of Kv1.3 currents were not voltage-dependent. In inside-out patches, tetraethylammonium (TEA) produced a rapid block of Kv1.3 currents upon the onset of a voltage pulse, while the inhibition by nystatin developed slowly. When co-applied with TEA, nystatin potentiated the extent of the TEA-dependent block, and the kinetic effect of nystatin was slowed by TEA. In summary, nystatin, a compound frequently used in perforated patch recordings to preserve intracellular dialyzable components, specifically inhibited the potassium channel Kv1.3 at concentrations well below those required for perforation



KCa3.1 is related to acute immune responses and Kv1.3 is related to chronic immune responses, the combined administration with Kv1.3 and KCa3.1 inhibitors is likely to enhance their effects in autoimmune disorders or graft rejection

We know that Kv1.3 is widely expressed in the brain, but is it expressed in the intestines of people with inflammatory/auto-immune conditions?

We do not have far to look and since we know that ulcerative colitis is comorbid with autism, we can stick with that


Abstract

BACKGROUND AND AIMS:

Potassium channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are markers of active UC. We hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine production in patients with UC.

METHODS:

Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3(+) T-cells after pharmacological blockade of KV1.3 and KCa3.1.

RESULTS:

Active UC KV1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that KV1.3 protein was present in inflamed mucosa in 57% of CD4(+) and 23% of CD8(+) T-cells. KV1.3 was virtually absent on infiltrating macrophages. KV1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R(2)=0.61) and IL-17A (R(2)=0.51), the mayo endoscopic subscore (R(2)=0.13), and histological inflammation (R(2)=0.23). In-vitro blockade of T-cell KV1.3 and KCa3.1 decreased production of IFN-γ, TNF-α, and IL-17A.

CONCLUSIONS:

High levels of KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. KV1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.


So now we have some evidence that Kv1.3 is involved in the inflammatory response within the intestines of people with inflammatory bowel disease (IBD).

Now we just need to look at what happens when you give Nystatin to people with IBD.

Since we do have to link all this back to Candida, let us look for people with IBD claiming that the problem was all about Candida.

If you google Crohns disease (a type of ulcerative colitis/IBD) you will find numerous reference to the benefit of Nystatin and again the assumption that “yeast overgrowth” is somehow the cause of the disease.  Lots of "holistic" doctors etc.


Why do so many people with autism benefit from Nystatin?

We have seen why some people with GI inflammation should find Nystatin very helpful, it will act locally as an immuno-suppressant.  

By reducing this inflammation there will be a reduction in inflammatory cytokines like IL-6.  But the whole idea of Nystatin being safe for children with autism is that it does not enter the blood stream, in stays inside the intestines.


Leaky Gut

Many people subscribe to the notion of the “leaky gut” in autism.  If indeed the gut was leaky, the Nystatin might leak out.  It would then act as a Kv1.3 blocker elsewhere in the body.  It may, or may not, be able to cross the blood brain barrier.

There is now some scientific evidence to show that  “leaky gut” is a real phenomenon.

In people with ulcerative colitis, of course the gut is leaking.  Blood is coming in and therefore other things can flow the other way.

In healthy people, Nystatin will stay almost entirely where it should, within the intestines.  In people with “leaks” it would seem likely that some will leak out.  In these people we might expect a greater effect.

We do know that inflammatory activity within the gut can transmitted elsewhere in the body via the vagus nerve.  This means that reducing inflammation within the GI will reduce the pro-inflammatory signalling sent around the body via the vagus nerve, even with no "leaky gut".  

This may indeed sound very odd, but very promising results are now being found in treating people with arthritis (an inflammatory condition, where IL-6 plays a key role) using implanted electrical devices that affect the vagus nerve.  Vagus nerve stimulation is not pseudoscience, even though it does sound like it should be.

  
My conclusion

The “father” of ARI and the DAN movement, Dr Bernard Rimland, a research psychologist, suggested that a small proportion of people diagnosed with autism had nothing more than an overgrowth of candida, caused by the frequent use of antibiotics.

It does seem that very many things can lead to “autism” and this diagnosis is now equally applied to people with very mild symptoms and those with debilitating ones.  I imagine that Bernie may indeed have been right; in a small number of people the problem may indeed be yeast.  However, given the relatively large number of people with autism (and IBD) who find Nystatin very helpful, I think the real issue is inflammation and  KV1.3.  The people who respond to Nystatin would very likely also respond to those TSO helminths, and even Stichodactyla toxin (see later).

One problem with regular use of antifungal medication is that you are going to kill off not just the candida.  A healthy gut is supposed have all sorts of things living in it.   

For me, the conclusion is to go back to the ion channels and look not just for KV1.3 blockers but also KCa3.1.  There are plenty of people doing just this, but not for autism, for example:-




Kv1.3 blockers do exist and they include:-

·        Curcumin (problem is low bioavailability)

·        Acacetin (rarely studied and mainly used by bodybuilders)

Abstract

Under normal conditions in the brain, microglia play roles in homeostasis regulation and defense against injury. However, over-activated microglia secrete proinflammatory and cytotoxic factors that can induce progressive brain disorders, including Alzheimer's disease, Parkinson's disease and ischemia. Therefore, regulation of microglial activation contributes to the suppression of neuronal diseases via neuroinflammatory regulation. In this study, we investigated the effects of acacetin (5,7-dihydroxy-4'-methoxyflavone), which is derived from Robinia pseudoacacia, on neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells and in animal models of neuroinflammation and ischemia. Acacetin significantly inhibited the release of nitric oxide (NO) and prostaglandin E(2) and the expression of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV-2 cells. The compound also reduced proinflammatory cytokines, tumor necrosis factor-α and interleukin-1β, and inhibited the activation of nuclear factor-κB and p38 mitogen-activated protein kinase. In an LPS-induced neuroinflammation mouse model, acacetin significantly suppressed microglial activation. Moreover, acacetin reduced neuronal cell death in an animal model of ischemia. These results suggest that acacetin may act as a potential therapeutic agent for brain diseases involving neuroinflammation.

·        Progesterone (as a hormone, has many other effects)

·        Verapamil (already in the PolyPill)



The most unusual/interesting comes from Cuba:-

Stichodactyla toxin





In humans, a polymorphism in the Kv1.3 promoter is associated with impaired glucose tolerance and with lower insulin sensitivity (11). These results suggest that selective Kv1.3 blockers might have use in the management of obesity and insulin resistance


Because pancreatic beta cells, which have Kv3.2 channels, are thought to play a role in glucose-dependent firing, ShK, as a Kv3.2 blocker, might be useful in the treatment of type-2 diabetes.
  
You may recall we already saw in this blog the older people taking Verapamil (for heart problems) did not develop type 2 diabetes. According to the table below, ShK toxin is a Kv3.2 blocker in humans, but Verapamil only works in rats.








Since it looks like selective Kv1.3 blockers may prevent/treat obesity, you can expect them to be attractive targets for pharmaceutical companies.  This is a disease of the 21st century.

The spin-off might later be a cost-effective treatment for inflammatory conditions like IBD and autism.

The clever new arthritis treatments, that could be used in autism, are hugely expensive.






Wednesday, 16 July 2014

Verapamil for a Broader sub-group of Autism and even Diabetes?



This blog is about science rather than medicine, and believe me there is a much bigger difference than you might hope for.
Many aspects of the research literature indicate the potential of certain calcium channel blockers, like Verapamil, to be useful in treating autism.  As we have seen, there are many different causes of autism and what treatment works in one type may be totally ineffective in another type.

For almost a year Monty, now age 11 with ASD, has taken Verapamil to control the behavioural effects of allergy that are driven by so called “mast cell degranulation”.  His pollen allergy makes his summertime behaviour dramatically worse; a reaction that is almost entirely reversed by Verapamil.

In my page in this blog on Allergies and Autism I raised the question as to whether Verapamil would be effective in treating the many people with autism who have food allergies leading to gastrointestinal (GI) problems.  Many people with autism have symptoms like Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD) and these are widely associated with worsening autistic behaviours.  Monty has no GI issues or food intolerance.  I was very interested to receive some lengthy comments from a mother with a son who does have autism plus GI problems.  She found Verapamil highly effective in treating both his GI problems and the autism.  This is rather significant, since while I do receive the odd comment that H1 antihistamines have an unexpected beneficial effect on autism, which supports some of my own findings and theories, the issue of GI problems is very common in autism.  Could a pill called Verapamil be the little wonder for them as well?  The science does indeed support this, even if current medicine does not.

 

How can medicine be so disconnected from science?  It does seem to happen far more often than it should.

I did wonder if I was missing something about Verapamil.  It is an L-type calcium channel blocker and in autism there is a known genetic dysfunction (CACNA1C) that affects the calcium channel (Cav1.2) blocked by Verapamil.  It also turns out that Verapamil has been shown to be a highly effective mast cell stabilizer.  I did a little more digging and found something very surprising, the effect of Verapamil on the pancreas.  The pancreas makes all kinds of enzymes as well as insulin.  In some people with an auto-immune dysfunction the body destroys its own insulin producing cells and diabetes results.  In some people with autism (also an auto-immune condition) the pancreas seems not produce some of the other enzymes and there are various DAN-type treatments for this; and the new CUREMARK drug CM-AT seems to target this dysfunction.

Science has remarkably shown that Verapamil had the potential to reverse diabetes, if intervention is early.  Given that type 1 and type 2 diabetes are becoming increasingly common and account for a substantial part of national healthcare costs, it seem odd that medicine has not taken full note.



It appears that older people on Verapamil for hypertension, strangely do not develop type 2 diabetes, which supports the claim for Verapamil.

There is no mystery as to why this is happening.  Calcium channels are widely expressed in pancreas, just as they are in the heart and the brain.  The effect of aberrant calcium channel signalling does no good for the brain in autism and in some other people, with a tendency to auto-immune problems, it would appear to be the pancreas that suffers.

You will recall that autism is amongst, other things, an auto-immune condition.  If you look at the extended family you will likely notice other auto-immune conditions like diabetes, thyroid problems, and arthritis.  (I would myself add fibromyalgia and even some types of chronic headaches to this list)

Recall that several drugs that help autism have a beneficial effect in diabetes and that the key type 2 drug for diabetes seems to have a positive effect on autism.

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes


In the above post we saw that PPAR gamma (PPARγ) is a nuclear hormone receptor which modulates insulin sensitivity.  The following autism study looked at the effect of a common diabetes drug, pioglitazone (Actos), an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. 
 

Pioglitazone is currently in Phase 2 trials for autism.

Another comorbidity of autism that is an auto-immune condition is asthma.  Here again, Verapamil was shown many years ago to hold promise.

Verapamil in the prophylaxis of bronchial asthma

A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced bronchoconstriction in 8 out of 16 asthmatic subjects (maximum increase in PD20FEVHi 416%). There was still significant protection (Δ PD20FEV1Hi>100%) in the responders 5 h after the oral dose.

I also noted in earlier posts that anti-oxidants seem to reduce the insulin required by diabetics and also improves one of the big problems that occurs along with diabetes that is peripheral neuropathy.  These antioxidants, like ALA, NAC, Thioctacid etc are also chelators of heavy metals.  While the planned study of chelators in autism in the US was effectively “banned”, a large study was carried out on heart patients.  Chelation was shown to be remarkably beneficial, but chelation is really just a shock dose of antioxidants.

Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction The TACT Randomized Trial


My take on this is that in many medical conditions, oxidative stress is present and therefore any antioxidant will be beneficial, but some more so than others.  In the well-researched world of asthma they concluded that the most potent, safe antioxidant was NAC (N-acetylcysteine).  NAC is my choice for autism.


Conclusion

If you have autism and suffer from chronic GI problems, Verapamil might well offer significant relief.

If you have unexplained autism flare-ups, like aggression, in summer this may well be driven by a pollen allergy, Verapamil is likely to help.

If your older relative has hypertension already and looks likely to be heading towards type 2 diabetes, maybe suggest they talk to their doctor about Verapamil;  it may well treat both.

Incidentally, if you have a child with autism and suffer yourself from chronic headaches or fibromyalgia, you might want to try some Verapamil yourself.

Verapamil is a very cheap generic drug; one tablet cost a couple of cents/pence. 


Opinion

I continue to be surprised how far medicine is behind science.

In the case of autism there is now a great deal of “actionable” research that is available for anyone to read.  This blog is about autism, but it seems that in many other areas of medicine the same is true, for example diabetes and types of cancer.   

The idea is that you should wait for clinical trials.  But who do you think is going to do them? There is no financial incentive for drug firms to do trials on old generic drugs for new uses.  Prepare for a long wait.

The medical practitioners involved with autism, mainly psychiatrists if anyone, show little interest in any novel treatment that has not yet been approved.  With such little interest from clinicians, novel treatments will remain well kept secrets for decades to come.

The “alternative” practitioners dealing with autism, like DAN doctors, are mainly in the US; but they are not fully grounded in science and seem overly interested in unorthodox expensive lab tests and costly supplements.

So you really do have to figure out autism for yourself, if you want to control it.  



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.  
Abstract
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


Abstract
 
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.
Abstract
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. 

Abstract


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.

Abstract

BACKGROUND:


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.

OBJECTIVE:


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.

METHODS:


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.

RESULTS:


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.

DISCUSSION:


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.

CONCLUSION:


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
 

Conclusion

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.