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Thursday 6 October 2022

Different L-type Calcium Channel Blockers Repurposed for Different Types of Autism

 

 A Purkinje Neuron, home of P-type calcium channels

Today’s post was prompted by a reader who saw a very positive response from the L-type calcium channel blocker, Amlodipine.

So we return to the subject of calcium channels.

The good news about calcium channel defects is that many are easy to treat.

In most single gene autisms (Rett, Fragile-X, Pitt Hopkins etc) the underlying problem is that a faulty gene does not do its job of producing the expected protein.  This is a problem of too little.

In many ion channel dysfunctions the problem is not too little, it is too much expression. For example, in Timothy Syndrome the mutation in the gene produces too much of the protein, in this case the L-type calcium channel Cav1.2.

Ion channel dysfunctions can be the result of a faulty gene, or just that the on/off switch for that gene is faulty.  Fortunately, the problem is usually that it is stuck “on”.

In people who develop Type-1 diabetes we have seen how the disease process can be halted by blocking Cav1.2 in the pancreas.  This halts the decline in the beta cells that produce insulin.

Once all the beta cells are dead, the person cannot produce insulin and has type-1 diabetes. Treating the person after this point with a Cav1.2 blocker will provide no benefit; the damage has already been done

Something similar happens in Parkinson’s disease, but this time you need to block Cav1.3.  In the early stages of the disease Cav1.3 is over-expressed in a key part of the brain, which triggers a slow process of degeneration. Treating a person with all the visible symptoms of Parkinson’s with a Cav1.3 blocker will provide no benefit; the damage has already been done.

 

Calcium channel blockers are not very specific

The current drugs used to block calcium channels were mainly developed to treat heart conditions.

When treating neurological disorders like autism we are primarily focused on the brain, what goes on elsewhere can also be very relevant, but in an indirect way.

In the brain the important calcium channels are: -

L type

N type

P type

R type

T type

Plus, Inositol trisphosphate receptor (IP3R) and Ryanodine receptors. IP3R has been covered in previous posts.


Verapamil (a Phenylalkylamine class drug)

Verapamil blocks L type channels and T type channels, plus some potassium ion channels.

When it comes to specific L type channels there are 4, Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

In the brain we have just Cav1.2 and Cav1.3. Verapamil mainly affects Cav1.2.

 

Amlodipine (a Dihydropyridine class drug)

Amlodipine blocks L type channels and N type channels.

Amlodipine mainly affects Cav1.3.

 

Nicardipine (a Dihydropyridine class drug)

Nicardipine blocks L type channels and N type channels.

As a Dihydropyridine, it should mainly affect Cav1.3.

In addition, it blocks the sodium ion channel Nav1.8.

The effect on Nav1.8 is why it has been proposed as a therapy for Pitt Hopkins. In this syndrome Nav1.8 is over expressed as a downstream consequence of a mutation in the TCF4 gene.

 

Effect on P channels

To some extent Verapamil, Amlodipine and Nicardipine all block P channels.

P channels are called P after the Purkinje neurons, where they are located. These Purkinje cells likely define some aspects of autism, because of their absence. Purkinje neurons are among the largest in the brain, with elaborate dendritic arbor.  I imagine this makes them vulnerable.




In the people with severe autism most of the Purkinje cells appear to have died.

Blocking P channels might have protected Purkinje cells from death.

 

The effect of too much L-type calcium channel signaling on behavior 

You can both turn on self-injury via activating L type calcium channels and extinguish it by blocking the same channels.  It is proven in mice and seems to apply to at least some humans.

Calcium channel activation and self-biting in mice

The L type calcium channel agonist (±)Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.

The self-biting provoked by (±)Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine. However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

(±)Bay K 8644 functions as an L type calcium channel activator that increases calcium fluxes in response to depolarizing stimuli (). In rodents, this drug has been reported to produce characteristic motor abnormalities including impaired ambulation, twisting and stretching movements, transient limb extension, back arching, spasticity, ataxia, or catatonia (). Some studies have anecdotally noted the occurrence of SIB with this drug (), though this phenomenon has received little attention. The current study shows that (±)Bay K 8644 will reliably provoke SB and SIB under certain conditions in mice, providing a tool to study the neurobiology of this unusual behavior.

 

When I first encountered the above study, I did wonder why Verapamil did not extinguish the self-injury.

It turns out that Bay K 8644 is a modified version of the common drug nifedipine, which is a Cav1.3 blocker.  Verapamil is mainly a Cav1.2 blocker.  Bay K 8644 is like the opposite of nifedipine.

In the trial they have activated Cav1.3 causing excess calcium inside neurons. The only way to block this process is to block Cav1.3. Blocking Cav1.2 with Verapamil could not solve the problem. 

Note that activation of Cav1.3 can cause motor abnormities in mice and this might be seen as ataxia in a human. One particular reader of this blog will see the relevance of this. 

I did write extensively in earlier posts about the large amount of research that links L type calcium channels to neuropsychiatric disorders.

I did mainly focus on Cav1.2 using Verapamil, but the evidence for the role of Cav1.3 is clear as day. 

L-type calcium channels as drug targets in CNS disorders

 L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value.

 

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms.

The L-type calcium channels (LTCCs) Cav1.2 and Cav1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder.

Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Cav1.2- and Cav1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

 

Was I surprised that Amlodipine, that targets Cav1.3 rather than Cav1.2, was very beneficial in someone with severe autism?  Not at all.

I was interested that the effect was more pro-cognitive than anti-anxiety.  Is that the effect on Cav1.3 or is it via that N channel Cav2.2?

N-type calcium channels are important in neurotransmitter release because they are localized at the synaptic terminals. Piracetam, the original cognitive enhancing drug, is also a N type channel blocker.

  

Statins and L type calcium channels blockers – it matters which one you choose

We previously saw how the statin class of drugs can be beneficial in autism, but it depends which one you chose. For example, in SLOS (Smith-Lemli-Opitz syndrome), where both copies of the gene DHCR7 are mutated, you need to push the gene to work. To increase expression of this gene you need Simvastatin. This is hard for people to understand because SLOS features very low cholesterol and statins are thought of as cholesterol lowering drugs. The body needs the enzyme DHCR7 to make cholesterol and Simvastatin increases DHCR7 expression.

In the case of L type channel blockers, the selection is very important.  The effect will not be the same.

If you have a mutation in Cav1.2, you would expect Verapamil to be a good choice.  If the mutation is in Cav1.3, you would expect Amlodipine to be better.

If you have over expression of T channels (Cav3.1, Cav3.2 or Cav3.3) then you would expect a benefit from Verapamil and none from Amlodipine.

If you have over expression of the N channel (Cav2.2) then you would want Amlodipine

If you have over expression of the sodium channel Nav1.8 then you would want Nicardipine

  

Conclusion

It is likely that many people with autism, bipolar, ADHD or schizophrenia might benefit from treating their ion channel dysfunctions.  The required drugs are cheap generics that have been in your local pharmacy for a few decades.

Back in 2019 I wrote the post below:

Cheap common drugs may help mental illness

I highlighted a new study, using historic data from Sweden, that looked at the secondary effects of statins, calcium channel blockers and metformin on psychiatric hospitalization.

 

Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness

 

Question  Are drugs in common use for physical health problems (hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides) associated with reduced rates of psychiatric hospitalization and self-harm in individuals with serious mental illness?

Findings  In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalization compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists. 

We found that periods of HMG-CoA RI (statin) exposure were associated with reduced psychiatric hospitalization in all subgroups of SMI (Serious Mental Illness) and with reduced self-harm in BPD and schizophrenia.

Exposure to LTCC (L type calcium channel) antagonists was associated with reduced rates of psychiatric hospitalization and self-harm.

Periods of metformin (a type 2 diabetes drug) exposure were associated with reduced psychiatric and nonpsychiatric hospitalization across all SMI subgroups.

 

Use of L type calcium channel blockers reduces self-harm.

How much more evidence is needed?

I took an educated guess several years ago that Verapamil would tame summertime raging in my son.  It was the only calcium channel blocker I tried and it worked. This year we had the emergence of extreme sound sensitivity. My educated guess was that blocking potassium channels with Ponstan (Mefenamic acid) would resolve the problem, and it did.  

Treating ion channel dysfunctions (channelopathies) in autism clearly is not rocket science; it is just waiting to be attempted.







40 comments:

  1. Hi Peter,

    I've been recently following your posts. The information here is so profound, it blows my mind. Sorry if my question is dumb. I don't have science background. If all these channelopathies and other comorbidities are because of mis- expressed genes, can't they be addressed using HDAC inhibitors? Why do we have to go after every gene as it looks to me like a huge task and kind of like patch work?

    ReplyDelete
    Replies
    1. Janu, you cannot go after every gene, but you can target key ones in your specific case.

      HDAC inhibitors do modify gene expression, but will affect many genes which may or may not include the ones relevant to your case. For some single gene autisms they do look interesting, but the potent ones are very expensive and have side effects.

      Delete
    2. Any information on T-Type Calcium Channels and Autism?

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    3. T channels are implicated in neurological disorders. The problem is finding a safe and effective way to block them. I do not believe there is one.

      I do recall when treating the mouse model of Timothy Syndrome (over-expression of the L type channel Cav1.2) the researchers strangely did not use an L type blocker, they used something else which may have been a T type blocker. I remember writing to the researcher, because he has a son with severe autism and went on to be head of neuroscience at one of the big Swiss pharma companies.

      For the moment it is not easy to modulate T channels.(Cav3.1 Cav 3,2 and Cav3.3).

      Delete
  2. Question from the States. What test is available to test for these genes?

    ReplyDelete
    Replies
    1. Some people have miss-expression of these genes because they have an error in the genetic code in their DNA, which you can test for using genetic testing. Some readers of this blog are in this category.

      Most people likely have miss expression of these genes due to a downstream effect of some other fault(s). You cannot easily test for a miss expressed gene in the brain because you cannot take a sample for testing at the lab.

      Delete
  3. Hi, what do you recommend for CNTNAP2 mutations? Thanks!

    ReplyDelete
    Replies
    1. The CNTNAP2 gene is one of the largest in your DNA and it is associated with a very wide range of disorders from mild to severe.

      A very good summary is here:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369114/

      I also wrote about the gene in this post:

      From a SWAN to Chopra-Amiel-Gordon Syndrome and the emergence of “-like” syndromes, CNTNAP2 etc

      https://www.epiphanyasd.com/2022/02/from-swan-to-chopra-amiel-gordon.html

      If you have a case of Pitt Hopkin-like Syndrome-1, which is caused by CNTNAP2, I think you would need a very different therapy to a different mutation in CNTNAP2 that produced ADHD.

      In the case of this gene I think you will need to focus on the exact nature and location of the mutation, as is suggested in the above paper. There can be no simple recommendation.

      There may also be a second (or third ..) mutation in a different gene that has produced a combined effect with the CNTNAP2 mutation. This is based on the multiple hit theory.

      Delete
  4. Hello Peter, NAC Sustain is back in stock in the Jarrow website.

    ReplyDelete
  5. So, my daughter has been doing great lately. However, something came up, as improvement will often induce new problems. We all know that asd kids ‘insist on sameness’. Well, my kid never really did. However, what she does like is something that actually is routine, to adhere to that routine. So, if you actually routinely go on wednesday to grandma, she likes that to actually happen. Its not a big deal, but she prefers it.
    What recently started happening is that if we disrupt a routine, she will get pretty anxious. Its not that she will have anmeltdown or extremely stubborn request to make the routine happen, its that she won’t be able to properly enjoy the rest of the day.
    Any ideas how to approach this, medically?

    ReplyDelete
    Replies
    1. Occasional use of low dose of Propranolol, would be one pharmaceutical strategy. Depending on what other therapies are used, it should not have any side effects. The effect lasts a few hours. Check with the doctor.

      Delete
    2. (Propranolol Rage 20 mg Morning Evening) any thoughts of this use

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    3. Hi Peter what is a good dosing of propranolol for a 158 pound male.

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    4. Low doses have been used in autism to treat anxiety and high doses have been used to treat self injury and aggression.

      A low dose would be about 100mg split into 3 doses. A high dose would be 400mg split into 3 doses.

      I think it is best to start at a very low dose like 20mg three times a day. Just Google "autism dose propranolol" to find the research.

      Delete
  6. Clemastine fumarate (Brandname Tavegyl/Tavist/Dayhist) seems to have run out everywhere and pharmacies tell even they cannot order it. Anyone know if this is "for good" and "everywhere" or if the drug is obtainable in any of the European countries?

    ReplyDelete
  7. Hi Peter
    Please what dose of ponstan would you recommend for a 30kg child.I was reading up on the speech benefits and would like to give it a try as we haven’t had any breakthrough with speech .
    How long do you think it should be taken for .
    Kind regards
    Apinke

    ReplyDelete
    Replies
    1. Apinke, the dose for children with fever is 20mg/kg split into 3 doses per day. So that would be 200 mg three times a day.

      I suggest you try 200mg once a day for a week and see if there is a benefit.

      If there is a benefit, try a lower dose and see if it is maintained.

      At very low doses most people seem to have no side effects of any kind that might limit how long it can be taken.

      First see if there is a benefit.

      Delete
  8. Thank you I will try it and see .I was able to get the 250 mg from Malaysia called Hostan.Will try it from tommrow for a week and see how we get on with it .

    ReplyDelete
    Replies
    1. Apinke, give the pill in the morning. The greatest effect will be in the next few hours.

      Delete
    2. Apinke, note that Ponstan and the generic version are available in the UK without prescription, to treat period pain. Even in Superdrug. The cheap place to buy is Greece where it is OTC and used like ibuprofen or aspirin.

      Delete
  9. Thank you Peter I had ni idea it’s available in the UK.I have this morning and he was able to do some vocalisations though not sure if it’s coincidence .I will keep an eye.I will look for friends that go on holiday as well to Greece and see if I can get.

    ReplyDelete
    Replies
    1. Greece is much cheaper than the UK. 15 x 500 mg tablets costs less than 2 euro and they will happily sell you as many packs as you want.

      Delete
  10. Hi Peter, since I fell down the immune system rabbit hole, I thought I would post this here.

    So one theory of autism is maternal activation that produces an overabundance of IL-6

    https://njms.rutgers.edu/archives/spotlight/articles/Maternal-Infections-that-Produce-the-IL-6-Cytokine.php#:~:text=As%20a%20prominent%20cytokine%2C%20IL,Autism%20Spectrum%20Disorder%20(ASD).

    and if there is an increase in IL-6 cytokine's in the brain of autistic people

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114764/

    and an increase in IL-6 produces social deficits

    https://www.sciencedirect.com/science/article/abs/pii/S0889159121006462#preview-section-abstract

    and my favorite bumetanide study shows a significant decrease in IL-6.

    https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=9166783_41398_2022_1987_Fig2_HTML.jpg

    Wouldn't you think it would be prudent to lower IL-6?
    Bumetanide and Ivermectin both do this.

    Level 13: Action on IL-6 levels
    A study by Zhang et al. demonstrated that ivermectin suppressed IL-6 and TNFα production, two major components of the detrimental cytokine storm induced by SARS-CoV-2 and “dramatically reduced” IL-6/IL-10 ratio modulating infection outcomes [47, 60].

    https://www.nature.com/articles/s41429-021-00491-6

    -Stephen


    ReplyDelete
    Replies
    1. guy, the problem is ivermectin can't use everyday. we need the drug to use everyday and safe. any drug else recommend?

      Delete
  11. Hello Peter,

    I am currently reading your book- it is great and I have a thousand questions! This is only one of them: how do you test the possibility of ion channel dysfunction? Would WES elucidate the problems in its expression? Would the absence of Cav1. 2, Nav1. 2, Kv7 etc. in the WES results warrant a "no-issue" with ion channels function?
    Thank you!
    Marina

    ReplyDelete
    Replies
    1. Marina, unfortunately it is more complicated. Some readers of this blog do find an important channel has a mutation via WES. They then know that targeting that specific ion channel is likely to provide a therapeutic benefit, at some point.

      I say at some point because the mutation may not cause a problem immediately, it may cause a regression later in life, or maybe never. In one family the grandfather had headaches, the mum no symptoms but the child developed severe problems likely associated with this mutation shared within the family.

      Also, most people have differentially expressed genes (DEGs) for reasons other than a mutation. So WES does not rule out a treatable problem with ion channels.

      In conclusion, WES can be helpful, but it is only part of the picture.

      Delete
  12. Thank you, Peter. I am asking this because we did WES, and there were no mutation associated with specific genes mentioned above. Do you mean despite the absence of DEGs related to ion channels in WES, the child may still have problems with ion channels?

    ReplyDelete
  13. Sudhakar Vankamamidi1 August 2023 at 01:25

    Hi Peter, we used verpamil and saw reduction in hyperactivity and increased meaningful play. But it didn't stopped SIB. Moreover it may reduce body DAO and triggered histamine caused SIB for us. So can other two Amlodipine and nifedipine may help. Or should I use both verpamil and amlodipine together to get benefit.
    Thanks
    Sudhakar

    ReplyDelete
    Replies
    1. You have be very careful. It is wise to stick to just one L type channel blocker. Amlodipine has the big advantage of needing just one daily dose. I think the effect is slightly different to verapamil.

      Sadly there are very many causes of SIB and trial and error is the only way to find a solution.

      Delete
    2. Maybe Nifedipine could help...

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC24802/

      -Stephen

      Delete
    3. Stephen, yes I remember that study about self-biting mice. Readers do need to understand the blood pressure lowering and other effects that might limit use of this class of drug.

      Delete
    4. Peter/Sudhakar, Verapamil is also a TRPA1 antagonist. https://www.nature.com/articles/celldisc201724 .

      I know Peter likes Ponstan for it's effects as a TRPM3 antagonist. So I'm guessing TRPA1 antagonism should also have a helpful effect in Autism. However in that research they are not favoring Verapamil for it's effects on calcium channel blocking. Instead they are suggesting Duloxetine might be a good choice as TRPA1 antagonist. They also mentioned Ketotifen, But not sure if it will have an effect at low doses which they clearly not discuss about.

      Delete
  14. Hi Peter, can we try 2.5mg amlodipine. This should be fine i guess. Thanks for all the inputs.

    ReplyDelete
    Replies
    1. Try it and see if there is a benefit and is free of side effects.

      Delete
  15. Hi Peter, lately i noted that calcium channel blockers activate IL6 which may trigger pans for susceptible kids. So may be for pans pandas kids these channel blockers may be big no.
    Thanks
    Sudhakar

    ReplyDelete
  16. peter may I ask how yourself and others are sourcing Verapmil and Bumetanide? We are in the UK like yourself and struggling to get it

    ReplyDelete
    Replies
    1. People in the UK either have a doctor abroad or buy things abroad.

      Delete

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