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 neurotransmitterglutamate 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.
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 disordersby 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.
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.
Conclusion
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.
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
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.
Conclusion
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.
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 toN-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 chelatedivalent 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:-
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.
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 throughBoldyrev’s book, it does look possible that the chemical relationship
between GABA and Carnosine many also play a role.
Conclusion
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.
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.
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.
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.
