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Showing posts with label Nav1.1. Show all posts
Showing posts with label Nav1.1. Show all posts

Friday 5 February 2016

Propranolol, Autism and Sodium Ion Channels Nav1.1, Nav1.2, Nav1.3 and Nav1.5









When writing this blog I frequently wonder what happened to all the very clever people; why are these full-time paid researchers often missing the obvious?







Boy with severe headache and ASD, awaiting Propranolol


The answer is, with a few notable exceptions (Catterall, Ben-Ari etc), the clever ones do not study autism, they study things that are much better defined, rare things like Angelman Syndrome and, recently, Pitt-Hopkins Syndrome.  These researchers seem much more rigorous.  For example:-


David Sweatt (Pitt Hopkins)

Pitt–Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription



Edwin Weeber (Angelman syndrome)



So autism is left to what might be termed the Baron Cohen brigade.



Propranolol

Propranolol is a medication of the beta blocker type.  It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, performance anxiety, and essential tremors. It is used to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks.

It is a nonselective beta blocker which works by blocking β-adrenergic receptors.

While once a first-line treatment for hypertension, they do not perform as well as other drugs, particularly in the elderly, and evidence is increasing that the most frequently used beta blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.

Beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine(noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block all activation of β-adrenergic receptors and others are selective.

It is occasionally used to treat performance anxiety.   Given the effect (above) on the fight or flight response this is logical.

The sympathetic nervous system's primary process is to stimulate the body's fight-or-flight response. It is, however, constantly active at a basic level to maintain homeostasis.

Evidence to support the use in other anxiety disorders is poor.

But what the ever useful Wikipedia almost glosses over is the part I find more interesting:-



  
Now we have to hope that cardiologists prescribing Propranolol are fully aware of the role of Nav1.5 in the heart and its role in heart rate.  This has nothing to do with it being a beta blocker.

Hopefully neurologists prescribing it for certain severe headaches understand the role of Nav1.1 in the brain.

It would not surprise me if they did not.



Propranolol earlier in this Blog

Earlier in this blog there are comments regarding the use of low doses of Propranolol to treat anxiety in autism.

Some people report it works wonders, while for others it did nothing.


  


Propranolol in Autism Research


A study was published recently and a reader drew my attention to it, but there have also been a few others.

Blood pressure medicine may improve conversational skills of individuals with autism


An hour after administration, the researchers had a structured conversation with the participants, scoring their performance on six social skills necessary to maintain a conversation: staying on topic, sharing information, reciprocity or shared conversation, transitions or interruptions, nonverbal communication and maintaining eye contact. The researchers found the total communication scores were significantly greater when the individual took propranolol compared to the placebo.
"Though more research is needed to study its effects after more than one dose, these preliminary results show a potential benefit of propranolol to improve the conversational and nonverbal skills of individuals with autism," said Beversdorf

  

Effect of propranolol on verbal problem solving in autism spectrum disorder


Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study




Back to Channelopathies

There are 24,000 human genes, but a much more manageable number of ion channels.  For each ion channel or transporter, there is a gene that expresses it.

When ion channels malfunction, it is called a channelopathy.  Channelopathies are quite well researched and very common in autism.  Early on in this blog I simplified idiopathic classic autism with the following chart.

I suspect that people with channelopathies (Nav1.1, Nav1,2, Nav1.3) caused by dysfunctions in the genes SCN1A, SCN2A, SCN3A are the ones that will most benefit from Propranolol.

I suspect those people will already suffer terrible headaches and/or seizures.

These three channelopathies have been known to be associated with autism for ten years.









Nav1.1 / SCN1A


Migraine, other headaches
Epilepsy


Regular readers will know that Professor Catterall is the expert on sodium channels and here he is again below




Nav1.2 / SCN2A

http://ghr.nlm.nih.gov/gene/SCN2A

Epileptic encephalopathy, early infantile, 11 (EIEE11): An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG


Nav1.3 / SCN3A


neuronal hyperexcitability and epilepsy 

         Novel SCN3A variants associated with focal epilepsy in             children.





Nav1.5 / SCN5A

http://ghr.nlm.nih.gov/gene/SCN5A

Mainly heart conditions, since this ion channel is expressed mainly in the heart.




Autism and Nav1.1, Nav1.2, Nav1.3

For many years it has been known that the hundreds of variations in the genes SCN1A, SCN2A and SCN3A are associated with autism.  So we can consider them pretty well established autism genes.

Clearly any drug affecting expression of those genes, or affecting the ion channels they express, should be a target autism drug.






Conclusion

Some people with autism and severe headaches, or epilepsy, have an underlying sodium channelopathy.  Sodium channel blockers are not as well understood/ developed as calcium channel blockers.

In some cases, but maybe not all, this should be detectable by genetic testing of the genes SCN1A, SCN2A and SCN3A.

If you live in a country that does not bother with genetic testing, you might want to fall back on trial and error and discuss Propranolol with your doctor.

Did all the people with Asperger’s, in the recent study, who became more conversational after a single dose of Propranolol, have problems with Nav1.1, Nav1.2 or Nav1.3 ?  I doubt it.  The other commonly known effects of Propranolol should also play a role.

But for a sub-set of people with Strictly Defined Autism, Propranolol might be hugely beneficial.  Perhaps Professor Catterall should investigate?









Wednesday 19 August 2015

Low Dose Clonazepam for Autism - SFARI Webinar with William Catterall








This post will be mainly of interest to the small number of people using low-dose clonazepam for autism and those considering doing so.

This therapy modifies the excitatory/inhibitory (im)balance between the GABA and Glutamate neurotransmitters.  The big advantage is that it should be very safe, is extremely inexpensive and, unlike Bumetanide, does not cause diuresis.   The disadvantage is that the effective dose is only in a narrow window, and you have to find it by trial and error.


Does it work?

It certainly does work in some children with autism.

It also appears to have an additional effect over Bumetanide alone, at least my son.

Questions remain:

·        Does it work with everyone who responds to bumetanide?
·        Does it only work in people with a Nav1.1 dysfunction?
·        Will bumetanide work in everyone who responds to Clonazepam?


One of my earlier, detailed, posts on this subject is this one:-



Just google “clonazepam epiphany” or use the site index, for the other posts.


Professor Catterall

I have already covered the science behind low-dose Clonazepam and Professor Catterall’s trials in two mouse models.  It is quite a complex subject and in the end most people just want to know does it work in humans with autism or not.

Catterall’s research was funded by the Simons Foundation, so no surprise really that he made a Webinar for SFARI.  It covers the ground of those two papers and indicates the next steps for his research.

It is a bit lighter going than his papers, but it is a full hour of science.

Catterall plans to trial it in humans with autism, starting with those known to have sodium channel dysfunction. So he is following the same pattern he used with his mice.

The first mouse model he used was Dravet syndrome, a rare condition leading to epilepsy and autism which is caused by a sodium ion channel (Nav1.1) dysfunction.  The second experiment used a standard mouse model of autism called the BTBR mouse model, so no connection with sodium channels.

My question to Catterall was whether this therapy would only work in people with a Nav1.1 dysfunction.  He did respond via the comments on the post, but did not really answer the question.  The fact that he plans to trial his idea on humans with autism with a known sodium ion channel dysfunction, does suggest something at least.

I think that since the actual mechanism of the drug is on a sub-unit of the GABAA receptor, sodium channels may actually be more of a coincidence, meaning that while autism Nav1.1 dysfunction may indeed indicate this therapy, it may be applicable in other autism where GABA is dysfunctional.


Bumetanide Use

The downside of bumetanide use to correct the E/I imbalance often found in autism is the diuresis and excessive loss of potassium in about 20% of people.

If you revisit the original paper suggesting an  E/I imbalance might be fundamental to many kinds of autism, you will see that this E/I imbalance is not just an ongoing issue, it is potentially an avoidable cause of disruption at key points in the brain’s development prior to maturation. In simpler terms, an E/I imbalance during development may cause the physical brain abnormalities often observed in autism.

That would suggest you should try and reverse E/I imbalance as soon as possible, well before maturation of the brain. 

One day an analog of bumetanide may be developed, that avoids the diuresis;  it is already being discussed.


Bumetanide (or low dose Clonazepam) use, even before autism has become established ?


In something like 30% of cases of classic autism there is macrocephaly (a big head), which even shows up on ultrasound scans of the pregnant mother.  A big head does not necessarily mean autism, but specific types of autism are clearly associated with big heads.

There are many other well known risk factors, like siblings with autism, siblings with other disabilities, older parents, family history (schizophrenia, bipolar, auto-immune conditions, COPD, Nobel Laureates, math prodigies) etc.

Since we also know that an indicator of this kind of E/I imbalance is that benzodiazepine drugs can show paradoxical effects (they work in reverse), it should be possible to make some kind of predictive diagnostic test.


So it would not be rocket science to identify many babies at elevated risk of autism and then treatment could be started very early and well before brain maturation.

This is rather like the Japanese researchers in the previous post suggesting that sulforaphane consumption in childhood might prevent susceptible people developing schizophrenia in adulthood.








Monday 19 January 2015

Modified Use of Anti-Epileptic Drugs (AEDs) at Low Doses in Autism

As readers will be aware, many people with more severe autism are also affected by epilepsy.  Siblings of those with autism also seem to be at greater risk of epilepsy.

There are frequent comments that once starting on AEDs (Anti-Epileptic Drugs) aspects of autism also seem to improve.  This should not be surprising given the suggested action of these drugs and the overlapping causes of epilepsy and autism.

Today’s post is prompted by the observation that in very low, apparently sub-therapeutic, doses some AEDs seem to improve autism in some cases.  This is relevant because the usual high doses of these drugs are associated with some side effects and indeed a small number can be habit forming.


What is epilepsy?


The cause of most cases of epilepsy is unknown.

Genetics is believed to be involved in the majority of cases, either directly or indirectly. Some epilepsies are due to a single gene defect (1–2%); most are due to the interaction of multiple genes and environmental factors.  Each of the single gene defects is rare, with more than 200 in all described.  Most genes involved affect ion channels, either directly or indirectly. These include genes for ion channels themselves, enzymes, GABA, and G protein-coupled receptors.

Much of the above applies equally to autism, including the genetic dysfunctions associated with GABA.  The ion channel dysfunctions in epilepsy are thought to be mainly sodium channels, like Nav1.1.  We previously came across this channel when looking at Dravet Syndrome.


Dravet Syndrome

Dravet Syndrome is rare form of epilepsy, but is highly comorbid with autism.  It is cause by dysfunctions of the SCN1A gene, which encodes the sodium ion channel Nav1.1.  There is a mouse model of this condition, used in autism research.  Dravet Syndrome is known to cause a down-regulation of GABA (the neurotransmitter) signaling.  We saw how tiny doses of Clonazepam corrected this dysfunction in mice.

Known ASD-associated mutations occur in the genes CACNA1C, CACNA1F, CACNA1G, and CACNA1H, which encode the L-type calcium channels Cav1.2 and Cav1.4 and the T-type calcium channels Cav3.1 and Cav3.2, respectively; the sodium channel genes SCN1A and SCN2A, which encode the channels Nav1.1 and Nav1.2, respectively; and the potassium channel genes KCNMA1 and KCNJ10, which encode the channels BKCa and Kir4.1, respectively.



Dr Catterall, the researcher, then went on to test low dose clonazepam in a different mouse of autism model and found it equally effective.  It also appears to work in some human forms of autism.


Sodium Valproate

Valproate is a long established epilepsy drug that has also been used widely as a mood stabilizer and particularly to treat Bipolar Disorder.

One side effect can be hair loss.  Hair loss/growth and also hair greying are frequently connected with drugs and genes linked to autism (BCL-2, biotin, TRH etc).

One regular reader of this blog has pointed out that a tiny dose of Valproate, when combined with Bumetanide, appeared to have a significant and positive effect.  We know that bumetanide works via NKCC1 and the GABAA receptor to make GABA more inhibitory.

Many modes of action are proposed for Valproate, but the most mentioned one is that it increases GABA “turnover”; so it would make sense that having shifted the balance from excitatory to inhibitory, a stimulation to increase GABA signaling might be beneficial.

What is odd is that this is happening at a dose 20 times less than used in epilepsy, bipolar or mood disorders.

The use of Clonazepam, discovered by Dr Catterall, is also at a dose 20 to 50 times less than the typical dose.

Clonazepam and Valproate are both AEDs.  There are not so many of these drugs and while using them at high doses, without dire need, might be highly questionable, their potential effectiveness at tiny doses is very interesting.

Clonazepam is a Benzodiazepine in the table below.






The above table is from the following paper:-




Low Dose Clonazepam

Low dose Clonazepam was shown to be effective by its action of modulating the GABAA receptor to make it more inhibitory.  There are different types of GABAA receptor and the low dose effect was sub-unit specific.  Other benzodiazepine drugs were found to have the opposite effect.

The mouse research showed that the effect only appeared with a narrow range of low dosages.


Low Dose Valproate

Valproate is known to affect sodium channels like Nav1.1, but also some calcium channels.

For an insight into some known potential effects of Valproate, here is a paper from the US National Institute of Mental Health:-




In the paper it highlights the less well known effects of Valproate:-

inhibits HDACs
Modulates Neurotrophic and Angiogenic Factors (BDNF, GDNF, VEGF)
PI3K/Akt Pathway
Wnt/β-Catenin Pathway
MEK/ERK Pathway
Oxidative Stress Pathways
Enhanced Neuroprotection
Enhancing the Homing and Migratory Capacity of Stem Cells

Here is a list of the suggested new applications of Valproate, many highly appropriate to many types of autism:-

*       A. Stroke
*       c. Anti-inflammation
*       d. Angiogenesis
*       e. Neurogenesis
*       b. Anti-inflammation
*       c. BBB protection
*       d. Angiogenesis
*       e. Neurogenesis
*       B. TBI


Having read that paper I am now not surprised that a tiny dose of valproate can have a positive behavioral effect in autism.  What would be interesting to know is how the effects and dominant modes of action vary with dosage.  I presume the dosage has been optimized to control/prevent seizures.

Valproate is a cheap drug and is available as a liquid, so accurate low dosing is possible.  It has been shown to be neuro-protective, even shown promise as a treatment for traumatic brain injury.

While not written about autism, some of you may find the following collection of research interesting:-




It does talk about the wider potential use of Valproate, but not at tiny doses.



Stiripentol

Interestingly, an orphan drug was developed in the European Union to treat Dravet Syndrome.  It is included on the list of AEDs above.

Even though that drug, Stiripentol, is not approved by the FDA, most sufferers in the US are able to acquire it under the FDA’s Personal Importation Policy(PIP).

So it is indeed possible to acquire drugs prior to approval in your home country.

Hopefully, once Bumetanide is approved for autism in Europe, similarly people will be able to access it easily in the US.

I wonder if anybody with Dravet Syndrome has tried low dose Clonazepam.  In theory it should be helpful.






Wednesday 23 April 2014

When Less is More - Tuning the Autistic Brain with Clonazepam





   
I cannot say whether there will ever be a “cure” for autism, but this blog has shown that certain types of autism can be treated today.  Actually, it is becoming much more like tuning.

Tucked away in the scientific literature, you can find that some receptors in the brain respond very differently to small stimuli than to large ones, I found this intriguing but thought little more of it.  Then, in the recent post on Glutamate receptors, I saw a chart from the MIT researcher that showed how using drugs you could increase/decrease protein synthesis in the brain, to optimize neural performance.  Rather like tuning the ignition timing on your car, some people were a little ahead of where they should be (Fragile X) and others were a little behind (Rett’s).  By using the right dose of either a positive or a negative modulator (of the mGluR5 receptor) you could tune the brain for optimal performance.



Source: Contributions of metabotropic glutamate receptors to the Pathophysiology of Autism





In the case of a recently investigated GABA dysfunction in autism, the drug is Clonazepam.  Tiny doses of this drug improve the performance of the neurotransmitter GABA, apparently by affecting the Nav1.1 ion channel.
In the research (on mice) it was shown that, within a tight dosage range, there was a measurable improvement in cognitive behaviour.  Too much, or too little of the drug and this benefit was lost.  So you would have to tune the dosing very carefully to get any effect.

It appears in humans things are more complicated than in mice, the small band of dosage where positive effects are seen does exist also in humans, but at slightly higher doses the effect turns negative before disappearing.




Source: Peter research


  
 This means that you have to get the dosage and timing just right to get the good effect.  Unlike tuning your car, where the effect is immediate, Clonazepam has a half-life of 30 hours.  This means that the concentration in the blood is made up of several doses from the last few days.

This made me realize what a challenge this would be to get right in other people.

I should point out that the same issue applies with TRH.  At the effective (also tiny) dosage you get a nice positive effect, but go too far and you get instant anger.  An Italian-Swiss researcher is using another analogue of TRH to treat some of the effects of aging.  He clearly had the same problem;  too much ended up having a bad effect.  Now he cycles one month on the drug and the next month with none.  TRH has numerous effects in different parts of the body, it has now been suggested that falling levels in middle age triggers hair to start to go grey.

With Clonazepam, along with some cognitive improvement, you also get very good mood, but at slightly higher concentrations happiness is replaced by anxiety. 

The effective Clonazepam dosage seems to fall over time; this is a very good thing, but further complicates getting things just right.  In high standard doses, the effect of Clonazepam normally reduces over time and patients need more of it.  The drug is normally used in doses 20 to 150 times higher to treat anxiety and seizures.

A further complication is that the optimal dose is 8% of the smallest available tablet.  The tablets do not dissolve nicely in water, you get a lumpy suspension.  As a result the dosage is always going to be a bit “hit or miss”


Conclusion

It looks to me that future autism treatment will include “tuning” specific dysfunctions with tiny amounts of drugs.

The good news is that tiny doses are far safer and less likely to have any secondary effects, than large doses.

The bad news is who is going to do the tuning?

People with Asperger’s, some of whom read this blog, will able to tune themselves; for others it will not be so easy.

In the case of Glutamate (mGluR5), the drugs required are still experimental.  In the case of GABA, they already exist.