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.
"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."
We have
noted in earlier posts that autism is a dynamic encephalopathyand 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 calledTNF-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 ofexcitatory and inhibitory circuits. Thus, increased IL-6 expression may
be partially responsible for the pathogenesis of autism.
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 antibodiesagainst 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 alphalevels
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.
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:-
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.
