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Thursday, 1 May 2014

Channelopathies in Autism - treating Cav1.2 with Verapamil





 
In December 2013 I wrote about a leading Italian researcher and clinician called Professor Antonio Persico and gave a link to an excellent presentation he gave in the US, about his views on the underlying biological process behind autism.




  
He had a nice graphic in which he depicted the puzzle that is autism.



  
One of his findings was that in the autistic brain there is an excess of both physical calcium and calcium signaling (via ion channels). He did not draw any therapeutic conclusions, which as I said was a pity.

In fact, Persico is far from the first scientist to point the finger at calcium channelopathies.

A few months before this, I had decided I would apply myself to see if there were any safe, practical therapies that could be applied, based on all the scientific research about calcium ion channels; incomplete as it might be.

After a few hours, or so, of reading about the biology of calcium channels, the available drugs and the existing research in their use in conditions other than autism, I came to the conclusion that Verapamil looked a very likely candidate.

Verapamil is a so-called L-type calcium channel blocker (L representing long-lasting length of activation); it particularly affects a type of voltage-gated calcium channel called Cav1.2.  For various reasons, I had deduced that these Cav1.2 channels were possible open more often than they should be in the brain of Monty, aged 10 with ASD.  I proposed that over activation of these channels resulted in extreme agitation that leads to aggression and self-injurious behavior in autism.

Back in September 2013, Monty was still having behavioral problems, apparently brought about by summertime pollen allergies.  I did write extensively about this and how I had narrowed the problem down to mast cell degranulation and histamine.  Treating the allergy did a lot of good, but was never a complete solution, since the standard allergy drugs worked for only a couple of hours, rather than the 24 hours they claimed.

So I had Monty in a state of near explosion by mid-afternoon most days, with a red face and letting us all know he was not feeling good.  He would say things including “be nice”, “I want to be nice”, “to hit your head” or even, on a good day, “to hit your head and see birdies”.  By then, he was also having Rupatadine, a mast cell stabilizer, which did seem to help.  The eruptions were far less often and less severe than in July, but it was clear that more could be done.

One afternoon, I decided to give a very small dose (20mg) of Verapamil, and before my eyes, the anger and agitation began to fade and was replaced by calm.  It was the most amazing experiment that I have witnessed and within 20 minutes there was complete calm.

In the following weeks, I would still hear Monty say “be nice”, but this was no longer followed by any aggressive behaviour.  The trigger was still there to energize these channels, but they had blocked by Verapamil.  It was like firing a gun, but with no ammunition; there was a “click”, but no “bang”.

This is the reason that Verapamil is in the PolyPill, in case anyone has wondered.

Before you start googling, there is absolutely no published research to support the use of Verapamil in autism.  This is part of the reason I did not to write about it at the time.

Verapamil is also a blocker of certain voltage-gated potassium channels and has the effect of raising potassium levels in the blood.  We have seen in earlier posts that potassium channel dysfunction is also present in autism and that raising potassium levels helps reduce sensory overload.  One effect of bumetanide is that it lowers levels of potassium, so bumetanide and verapamil are in that way very complementary.

Subsequently, I have read that mutation of the CACNA1C gene is associated with schizophrenia, which is like adult-onset autism.  The calcium channel produced from the CACNA1C gene is Cav1.2.  So this might be a case of what helps in autism might help in schizophrenia.


 If you are interested in why I decided to test Verapamil, read on.

 
Observations


Anger & SIB

Anger, leading to violence against others and to yourself are behaviours that arise in many people with autism.  There are undoubtedly many causes, and many are behavioral.  If a non-verbal person cannot express what he wants, or a partially verbal child has some pain (e.g. toothache) and does not understand it, things are likely to get out of control.

But there are other times, when for no apparent reason, nasty behaviour can occur, so I presumed that there might be a biological explanation.  If there was one, then I would think about a biological intervention.

My wife always asked Monty if his head was hurting when these kinds of behaviors popped up.  He would usually say “yes”, but it could well have been to avoid any other questions.  But why not consider it as possible that there is a pain prior to SIB.


Fever Effect

Then we have the recurring observation about autistic behaviours changing when the person has a high temperature; the fever effect.  This has now been studied by literally warming people up in hot water and then carrying out behavioural test.


As usual in autism, this effect applies much more to some people than to others.  Monty is moderately affected, but some people are dramatically improved.


Headaches

Headaches are very common, but some people do seem to get far more than their fair share.  Migraines are particular nasty and so is another type, the cluster headache.

Cluster headaches are severe headaches that are clustered together.

Cluster headaches are occasionally referred to as "alarm clock headaches" because of the regularity of their timing and they may awaken individuals from sleep. Both individual attacks and the cluster grouping can have a metronomic regularity; attacks striking at a precise time of day each morning or night is typical. This has prompted researchers to speculate involvement, or dysfunction of the brain's hypothalamus, which controls the body's "biological clock" and circadian rhythm.

Now I have noted that in some literature it is claimed that parents of children with autism often have a history of headaches (and I do not mean caused by dealing with their child’s autism).  

Note that most younger people with autism have a “faulty” biological clock, so they have trouble sleeping through the night.
 

Febrile seizures

Seizures and autism are closely related.  Febrile seizures occur in some children when they have a temperature greater than 38 °C (100.4 °F).  They are twice as common in Japanese children than they are in Western children, occurring in up to 9% of children and mainly in boys.

It is not agreed exactly what causes febrile seizures, Japanese research points to voltage-gated sodium channels, which does not really support my theory.  However, rather than delete this part of the post, I did a little more digging and found a paper in the Journal of Neuroscience that does neatly fit by theory.



Comorbidities

It is well documented that poor cardiac health is associated with autism.  I have commented before that it is not entirely by coincidence that some drugs that help autism were actually developed as drugs for heart problems.  By treating the autism, a side benefit is that you may also be treating (and perhaps avoiding) the heart disease that would otherwise likely to develop at quite a young age.

So, while giving statins and calcium channel blockers to a healthy young person would be irresponsible, the same may not true for people with autism.  In the same way that people with type 1 diabetes have been recognized as being at high risk of heart disease and are put on preventative drugs at a much younger age than the wider public. Patients with type 1 diabetes are 10 times more at risk from heart disease than other healthy patients.  They are recommended statins, aspirin therapy and an ACE inhibitor.  An ACE inhibitor reduces blood pressure in a different way to how Verapamil also lowers blood pressure.

Due to the severity of neurological/behavioral problems of autism, medical practitioners are not really worrying about cardiac health.


Too Much Calcium

There are opposing views about the role of vitamin D in autism; in other words, too much or too little.  There have been some interesting thoughts about milk and autism, and not about whether or not it is fortified with extra vitamin D; the point was the role played by calcium.

Then there is the mother who found that supplementing her autistic child with calcium had some frightening consequences, producing profound regression.



Basic Biology

If you want to read about the basic biology of calcium channels, here are links to Wikipedia;-





Connections with the biology

One of the things that drew my attention was the fact that the behaviour of some calcium channels is temperature dependent.  There are other ion channels that are also temperature dependent.  The Cav1.2 channels are known to behave differently according to their temperature.


Connections within the literature


Timothy syndrome

I have covered Timothy syndrome previously in this blog.

This is a, thankfully, extremely rare condition in which the most people do not survive to childhood; those few that do are likely to have autistic-like symptoms.

The syndrome is caused by severe mutations of the CACNA1C gene.  As a result it is also associated with severe heart problems, since this gene expresses the Cav1.2 channel that is found in the heart and the brain.


In the following article, Dr Ricardo Dolmetsch used an experimental L-type calcium channel blocker, called Roscovitine, to “successfully” treat his model of Timothy Syndrome.


Dolmetsch is now Head of Neuroscience at the Novartis Institute for Biomedical Research.  I did write to him once, when he was still at Stanford, to ask if he was interested in discussing some of my ideas – no answer, I guess he was busy curing autism.

Headaches

It has been known for many years that some L-type calcium channel blockers are effective in treating both migraine headaches and cluster headaches.


Individualizing treatment with verapamil for cluster headache patients

 

CONCLUSIONS:

Providing the dosage for each individual is adequate, preventing CH with verapamil is highly effective, taken three (occasionally with higher doses, four) times a day. In the majority (94%) with episodic CH steady dose increase under supervision, totally suppressed attacks. However in the chronic variety only 55% were completely relieved, 69% men, but only 20% women. In both groups, for those with partial attack suppression, additional prophylactic drugs or acute treatment was necessary.
This study found that some people required 5 times higher dose than others and doses were up to 960mg per day.

Verapamil in prophylactic therapy of migraine

We conducted a double-blind, placebo-controlled crossover study of verapamil HCI in the prophylaxis of chronic migraine headaches. Verapamil significantly reduced both headache frequency and duration with few side effects. The drug may be useful for a segment of the migraine population refractory to other prophylactic agents or for those who cannot tolerate the side effects of other drugs


Mice and SIB (Self Injurious Behaviour)

Lots of people do not like the idea of being compared to mice, or even worse rats.  Nonetheless, this following paper is indeed very relevant, it showed that it you active the L type calcium channels in mice they will engage in self injurious behaviour.


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.

If Monty was a mouse, verapamil would therefore likely not work and I would probably have had to use nimodipine.


Genes

I do not claim to be an expert in Genetics, but I can uses genes to support my case.

In 2013 a paper was published in the Lancet that looked for genetic links between a range of neurological disorders.



In this paper you can find out many things, including:-


  •  Gain-of-function mutations in CACNA1C causes Timothy syndrome
  •  CACNA1C is a susceptibility gene for bipolar disorder, schizophrenia, and major depressive disorder
  • neuroimaging studies have documented effects of CACNA1C variants on a range of structural and functional brain phenotypes, including circuitry involved in emotion processing, executive function, attention, and memory
  • Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia
  • CACNB2 encodes an auxiliary voltage-gated calcium-channel subunit that interacts with L-type calcium-channel subunits (including CACNA1C, CACNA1D, and CACNA1S) to promote their trafficking to the plasma membrane, increase their function, and regulate their modulation by other signaling proteins and molecules
Now “my” Calcium channel, also known as Cav1.2, is encoded by the very same CACNA1C gene.

In a similar paper, autism also gets a mention 

“Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders”


So all in all the genetic analysis also point to Cav1.2 as a good candidate for some intervention.


Epilepsy

Verapamil is being investigated to treat various forms of epilepsy and seizure.  This is interesting, since seizures are highly comorbid with autism.

Seizures tend to develop in early puberty in many cases of autism.  It appears possible (maybe not probable) that if you can avoid the onset of epilepsy during this time of hormonal change, you may be free of it for life.  The science has shown that the first seizure makes a biological change occur;  the same is indeed true with asthma.  If you can identify the at risk group (i.e. people with autism for epilepsy and atopic dermatitis for asthma) you may indeed be able to avoid it.

I was not aware of this until after Monty, aged 10 with ASD, had developed asthma, but I am well aware of it now.  I am actively taking steps to avoid epilepsy.

The other useful aspect of this research is that they are all clinical trials of Verapamil in children.  This is important from the safety perspective.








Choice of Channel Blocker

In medicine, calcium channel blockers were developed to treat heart conditions.  A common problem in treating autism is the need for drugs to freely cross the blood barrier (BBB); most do not.

Other issues include the half-life of the drug and most importantly the safety of the drug.

Given these considerations, and the fact that I know precisely which calcium channel I want to block, this led to me to Verapamil.

It is very widely used, and is available very cheaply as a generic in sizes down to 40mg.  Adult and indeed child dosages go all the way up to 400+mg a day.

Since the idea is to subtly affect the brain and not dilate blood vessels in the heart, which increases the supply of blood and oxygen; a small dose was envisaged, 20 mg.

On paper, Nimodipine, also looks a very interesting candidate, but it is rarely used in children.  It would be useful to trial it on adults with autism.  It works better than verapamil in mice with SIB.


Conclusion

I must admit that some of my “evidence” was gathered after I had proved my theory was valid, like the mice with SIB after their L-type channels were activated.

Given all of the “evidence” it does amaze me that it did not occur to anyone to try a drug like Verapamil in children with autism.

Clearly all drugs carry a risk, but so does violence and self-injury.


P.S.  Note that magnesium is also a calcium channel blocker







13 comments:

  1. How did you have verapamil to try on him? I am having a really rough time finding things without a prescription.

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    1. It really depends where you live. In the US there are many doctors prescribing drugs "off-label", based on some evidence that they might help. In some countries pharmacies follow the rules much less strictly. In some countries, like the UK, off-label prescribing is almost forbidden and pharmacies work by the book. Then people go to internet pharmacies.

      The rules are there to protect you, which is good. But then doctors have to keep an open mind to new uses of existing drugs, which they do not. The cost of approving an existing generic drug for use in autism is about $3 million, so it is not going to happen very often.

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  2. Hi Peter.

    Let me give you some general background on my son before I get to my questions.

    My son Wyatt is 4 yrs old and 17kg/37lbs. Starting around 18 months of age, many of the common signs of autism started appearing in my son. One of the unique issues my son has always had is an extreme aversion to chew and swallow solid food. When he was a baby, swallowing purees was not a problem. As we transitioned him to solids, he would try to swallow them whole without chewing, causing him to choke and gag. His diet became solely liquid based. He has been fed via G-Tube since.

    As I mentioned in a couple of other posts, he has always had issues with SIB and aggression. He was prescribed Risperdal. We went up and down in dosage, but never really saw any conclusive evidence that it did anything to alleviate this behavior. Wyatt also exhibits extreme anxiety and a lot of OCD behaviors. Guanfacine and Zoloft were also prescribed, but no tangible results were noticed. Over the past couple of months, this behavior has skyrocketed. It got to the point to where my wife and I had to pin him down in order to keep him from hurting himself or others. He was hospitalized in early November and admitted to the inpatient psych ward. While there, the Psychiatrists tried Seroquel, Abilify, Prozac, and a Clonidine patch. He got a mildly better and we were discharged.
    Extreme aggression, SIB, and OCD continued at home though. All throughout this ordeal, I was reading your blog and eager to try some of your therapies, but really did not know how to approach the doctors about them. I bought Super Sprouts and NAC, but did not want try them until after we got his raging under control. After surviving another day of rage with my son, one night my wife suggested that we just try the NAC and Sprouts. We did the following morning, and the results of broccoli sprouts + NAC were very noticeable. His mood changed from a constant state of agitation, to happiness. However, his OCD and anxiety is sky high, and a rage will occur if he or someone else cannot comply with some bizarre OCD demand he has.

    My son’s psychiatrist approved trying Verapamil. Since my son is fed entirely through a G-tube, tablets were out of the question. She had a compounding pharmacy make a liquid version based on a 50mg/ml. Our instruction was to take 0.2ml once a day. That works out to 10mg a day. We tried it yesterday morning, and did not see any improvement. In fact, my wife says it might have made things worse.

    0.2ml is extremely difficult to work with. The pharmacist explained that perhaps a lower concentration would work better. By the time 0.2ml travels through the tube into my son's stomach, I wonder how much an already tiny amount of liquid is really getting there.

    So we decided to stop Verapamil after 2 days. So far, the only thing we can conclude is that Verapamil does not work on my son, the dose is too small, or the tiny dose never really got there to begin with. Perhaps we will try it again if we can get a lower concentrated dose compounded for us.

    So after all of that, here are my questions.

    1. Are you aware if a test for excess calcium is possible? Perhaps there is for the blood, but would that mean anything about physical calcium and calcium signaling in the brain? It seems like a positive test would build a strong case for Verapamil.

    2. How did you come up with Monty’s Verapamil dose amount?

    3. We have noticed that most of my son's episodes with extreme aggression and SIB are triggered by a bizarre OCD request not complied with. Have any of your therapies had success with OCD?

    4. Another major problem my son has right now is extreme separation anxiety from his mom. I read your one of your posts last night about PANS. But, from what I can tell, PANS seems more like regressive autism in that it suddenly affects a normal child. My son fits the classic onset autism model. Is PANS something to consider though?

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    1. This comment has been removed by the author.

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  3. Hi JB, thanks for your extensive explanation.

    First of all, Wyatt’s problems with food texture and swallowing are not so unusual and neither is the separation anxiety when Mom has to leave.

    Some people are feeding purees to kids older than your son. The problem is that you may never be able to stop. The same is true for toilet training, problems going to the dentist, getting a haircut etc. The longer it goes on being a problem, the bigger the problem becomes. We know a boy aged 5 who “could not drink water”. In the end, no matter how awful the process might be, you have to go back to purees eaten with a spoon. Slowly introduce little lumps and then bigger ones.

    With SIB, some people let it play out. I just don’t allow it. I would do unexpected things like tipping my son upside-down, or getting down to the level of his eyes and bark like a dog, basically anything. Now he knows I will not allow SIB. The result is that now I can just sit him down, talk to him, redirect his attention and calm him. SIB is self-perpetuating and becomes an acquired behavior. In a small child it can be stopped without drugs. Drugs may stop it starting in the first place.

    My blog is all about drugs that can counter the underlying dysfunctions in autism, but even more powerful are the behavioral interventions. I recommend both. Some behavioral interventions require what comes down to “tough love” which many Mom’s find almost impossible.

    As you know, I have read a lot of medical research, but I am not a doctor.

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    1. (PART 2 - there is a limit on the number of characters)

      Here are my answers.

      1. Your bones are the body’s store of calcium. There is a lot of it. A simple blood test can tell whether the level of calcium in the blood is normal. The body uses calcium ions to send signals and so what really matters is the flow of calcium ions into and out of cells. You could have normal levels in your blood, but have a dysfunction somewhere in the “calcium channel signaling network”. Verapamil blocks a specific type of channel called “L type”. In particular it affects one called Cav1.2. This channel is actually a protein and it is controlled by a gene called CACNA1C. There are several known dysfunction in this gene, called SNPs, that are known to occur in autism and schizophrenia. So to check if Verapamil should work, it might well be possible to go to a gene lab and check Wyatt’s blood looking for Single Nucleotide Polymorphisms connected with this gene. But there are other calcium channels affected by Verapamil and also some potassium channels. I think the key gene it is CACNA1C, but it could be one that is associated with one of the other channels that Verapamil blocks.

      2. I read the research to determine if there was likely to be a calcium channel problem. I ended up with L types in general and Cav1.2 in particular. I reviewed the research on all the possible channel blockers for safety, use in neurological conditions, pediatric use etc. I ended up with Verapamil. I checked the safety aspect with various doctors. The smallest pill available to me is 40mg. There are very much bigger doses. I decided to test half of a pill. I crush it and it is taken as liquid with juice/water.
      I think 10 mg taken with food might have no effect in my son.
      We now use 40mg taken three times a day. If a stressful condition arises and he missed a dose, SIB can and does return, like yesterday. 10 minutes after Verapamil, peace is again restored.

      3. Aggression is often triggered by little things, like a missing Lego brick or the refusal to be given something that was expected. Here the best thing is the behavioral approach of getting used to surprises and not getting your own way. By being protective to a child, it is easy to make a small problem into a big problem. For example, my son used to get very upset by the sound of babies crying. The solution was to talk about why babies cry and to expose him to that very sound he hates, over time he builds up a tolerance and understanding. Now when he hears a child at school crying, he always goes to see what has happened.
      The use of NAC did make a big reduction in stimming and OCD.

      4. I am sure there are many un-named syndromes in autism, but problems separating from Mom are quite normal. PANS occurs very rapidly, so I doubt he has it. We had a huge problem when our son’s 1:1 assistant left after a few years. This triggered a year-long regression with lots of SIB.
      The solution is to introduce lots of people and not be dependent on any one person, even Mom. Then, when one favorite has to leave, it does not matter because another fun person arrives or fun activity starts. This may be easier said than done, but it is the solution.
      Fun people can be relatives, small children (probably girls) who want to engage with Wyatt, or a part-time student therapist. There are a surprising number of 20-25 year olds who really want to work/play/engage with kids with autism. They have a lot more energy than Dad/Mom. Look for people studying psychology or special education.

      I hope that helps.

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  4. Great information. My daughter is autistic and in Cortagen genetic test we found that she has a variant of uncertain significance in CACNA1C. We have been trying Verapamil in different dosages. Her Vocal stimming is increasing with 20mg or more dosage. We also see symptoms like passing more gas. Are these common symptoms with Verapamil. She doesn't have SIB but flops when she is upset. We are hoping Verapamil will help in reducing that kind of behavior.

    Thanks
    AG

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    1. Verapamil is Generally well tolerated but, as with most drugs, some people get side effects. If you give it with food you might avoid the gas, also some probiotics stop gas. I would only use verapamil if it has some positive impact. You may find changes over time, so if something develops in the future verapamil might become more useful.

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  5. Hi peter, you have done a great deal of research in autism. You not only share all the information you find out through your blog but also clarify doubts. I don't know what to say ..but thank you.
    Few weeks ago my daughter poured extra soap into her bath 'to make it more bubbly' but next day woke up with very itchy and persistent eczema all over her body(which won't go away). She has had eczema problem from birth. She is also allergic to tomatoes and many other foods and the symptom is 'gastric reflux' that makes her very uncomfortable. She doesn't have any major behavior problems like rage or aggression. I tried through different routes to help her but never thought about channelopathies. I'm trying to educate myself about ion channels and ion channel diseases. In the meantime I got hold of bumex. I don't know if I should try and address her allergies first before trialling Bumetanide...

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  6. There is a great deal of evidene to support the use of bumetanide, so it is well worth trialing it should you have the chance. You need at least one month. It is possible that severe allergy may mask the benefit.

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    1. Peter, allergies masked the benefits from NAC, verapamil and the MAD, but not the bumetanide in our case. Though behaviors such as irritation and sib came up with allergies, the cognitive improvements held on and continued to improve.

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  7. Hi Bhuvaneswari,

    Maybe try Zyrtec? It usually works for my allergies which are itchy skin, one eczema patch that will flare, creepy crawly feelings up and down my calves, dry nasal passages and shortness of breath, with borderline wheezing.

    My daughter had a lot of food sensitivities, on top of true peanut and sesame allergy. Many foods that she could not handle. Much of it resolved when we did the Specific Carbohydrate Diet. I modified it though, did not use the extensive nuts and honey and baking soda. Instead, my daughter ate meat, lot of butter and olive oil, egg yolks, well cooked veggies, nothing raw since fibre is pretty hard to digest. A few fruits such as bananas, all the berries. I basically followed the diet prescribed by Dr. Haas, in the 50's, who created it, rather than Elaine Gottschall's version. My husband also did it successfully for his chronic gi issues.

    The diet was not very difficult to do, and we have stayed close to it all these years, except occasional treats. It also made it very easy to transition to the MAD. MAD and verapamil have improved things quite a bit, to a point where she is now able to handle many different foods, even garlic which has always been hardest for her. If you would like more information, please feel free to ask.

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  8. The CACNA1C gene seems very interesting, (at least for rats).

    Gene associated with schizophrenia, bipolar disorder, autism, ADHD, and depression linked to brain cell death in mice. (easy-to-read)
    https://medicine.uiowa.edu/content/gene-associated-schizophrenia-bipolar-disorder-autism-adhd-and-depression-linked-brain-cell

    "The findings suggest that loss of the CACNA1C gene disrupts neurogenesis in the hippocampus by lowering the production of BDNF.
    Pieper had previously shown that the “P7C3-class” of neuroprotective compounds bolsters neurogenesis in the hippocampus by protecting newborn neurons from cell death. When the team gave the P7C3-A20 compound to mice lacking the CACNA1C gene, neurogenesis was restored back to normal levels. Notably, the cells were protected despite the fact that BDNF levels remained abnormally low, demonstrating that P7C3-A20 bypasses the BDNF deficit and independently rescues hippocampal neurogenesis."

    So what is that compound? From Wikipedia:
    "P7C3 is a drug related to latrepirdine (dimebon) which has neuroprotective and proneurogenic effects and may be potentially useful for the treatment of Alzheimer's disease and similar neurodegenerative disorders. The pharmacological effects of P7C3 in vitro resemble those of endogenous proneurogenic peptides such as fibroblast growth factor 1 (FGF-1)".. "The mechanism of action of the P7C3 series of compounds involves activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme responsible for the transformation of nicotinamide into nicotinamide adenine dinucleotide"
    https://en.wikipedia.org/wiki/P7C3


    /Ling

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