Verapamil, Autism, Summertime Allergy, Asthma and Eczema

As the symptoms get stronger, so does the therapy, 

going up in steps from May to July/August and then down to October

Today’s post is a practical one.  There is an interesting scientific one in preparation all about applying the emerging science of gene silencers and enhancers. 

I discovered in previous years that the summertime raging exhibited by Monty, now aged 12 with ASD, could be prevented using a small dose of the L-type calcium channel blocker, Verapamil.  Verapamil is also a mast cell stabilizer and blocks potassium channels linked to some inflammatory response.

This summer the story has repeated itself.  As the amount of airborne allergens increases from spring to summer the same seemingly mild allergy symptoms return.  So in late spring there was some sneezing and by mid-summer some eczema (atopic dermatitis) behind the knees and finally a very mild amount of asthma (slight wheezing); all of which were easily treated.

This apparently mild allergy triggers a flare-up in autism that is anything but mild.  To treat that the “silver bullet”, so to speak, is Verapamil.  It has a short half-life and so after 3-4 hours, depending on the initial dose, the effect is lost.  So in the peak of the allergy season, 20 mg every 4 hours provides near guaranteed protection.  Skipping a dose, like first one in the morning, will almost guarantee a mood change to agitation and then extreme anger.  That mood reverses within a few minutes of treatment again with Verapamil.

In late spring and early summer the use of allergy treatments (Azelastine, plus quercetin) and verapamil twice a day keeps things all under control.  But once the first faint signs of asthma reappear, due to the growing allergy effect, the only way to maintain normalcy is to make more frequent use of small doses of verapamil.  Using more antioxidants (NAC) does not have any effect; the verapamil addresses a summertime need.

In a previous post I did mention that I tried verapamil on a winter-time flare-up, just to see.  It had no effect whatsoever.  That problem was traced back to losing milk teeth and was solved with some ibuprofen, which was later replaced with Sytrinol/Tangeretin, the PPAR gamma agonist.  

Some children with autism are treated long term with Ibuprofen, or other NSAIDs, on a daily basis.  I have no doubt that it can be effective in specific cases, but the known side effects made me look for a safe alternative, which turned out to be Sytrinol.  Sytrinol has exactly the same effect as Ibuprofen, for this kind of flare-up, with no apparent side effect. Sytrinol is not a painkiller.

Since the roots of the final four milk teeth take several months to melt away and all the time levels of the inflammatory cytokine IL-6 are raised, there will be recurring behavioral flare-ups in those with the kind of over-activated immune system common in autism.  It seems plausible that the PPAR gamma agonist is down regulating  the activated microglia and thus blunting the immune over-reaction.  Anyway it works, for whatever reason.

The mast cells, degranulating due to allergens, release histamine and IL-6, the histamine causes further subsequent release of IL-6. Verapamil blocks this process.  The IL-6 released by the body to signal teeth to dissolve clearly is not reduced by Verapamil. 

The amount of inflammatory cytokines (IL-6 etc) produced by allergy is logically over a different order of magnitude to that used to signal milk teeth to dissolve.  The effect of Sytrinol is perhaps too mild to sufficiently dampen the response to the IL-6.   Maybe it helps somewhat, but I really cannot say one way or the other.

There seems to be a good case for Sytrinol year round and then Verapamil as required.  When I next update my Polypill formulation, Sytrinol will be included.

I think Verapamil likely has beneficial pleiotropic effects and so, in those who well tolerate it, it might be useful year round.  A small number of people do experience side effects.

     

Clinical Investigation vs Off-Label Treatment for Autism

Antonio Hardan, the psychiatrist at the Stanford School of Medicine, has published another paper.  Hardan is interesting, he is a clinician rather than a rocket scientist, but he gets involved in a very wide variety of clinical trials, usually of existing drugs that might be effective in autism.

In his latest paper, this time about Glutamatergic Dysfunction in Autism, he highlights the problems with clinical trials:-

·        Heterogeneity of autism

·        Subjective rating scales rather than biological measures.

In other words there is no single autism and there is no good way to reliably measure the efficacy of any drug tested on it.  Consider what that really means.

Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date

  

Hardan really should know about this, just look at the clinical trials he has been involved in:-

So why bother with Clinical Trials?

This may sound like a very unscientific question, but perhaps it is not.  A couple of years ago Roche pulled the plug on Arbaclofen, because it “failed” in its autism clinical trial.  Many parents thought it worked.  Now the Simons Foundation has acquired the rights to the drug and is restarting trials.  How many other trial drugs were prematurely brushed aside?

Many years ago the hormone secretin was put forward as a therapy for autism, particularly for people with GI problems.  Several expensive clinical trials later, it was determined to be ineffective.  But some people continued to rave about it.  Where they all deluded?

The very expensive IVIG therapy has also been put forward as a wonder therapy for autism.  The critics highlight that in studies 90% of people do not benefit and therefore the therapy has little value.  But what if you are in 10% that do respond very well?

Intravenous immunoglobulin treatment of children with autism.

Abstract

Since autism has been associated with immunologic abnormalities suggesting an autoimmune cause of autistic symptoms in a subset of patients, this study was undertaken to investigate whether intravenous immunoglobulin (i.v.Ig) would improve autistic symptoms. Ten autistic children with immunologic abnormalities, demonstrated on blood tests, were enrolled in this study. Their ages ranged from 4 to 17 years, with two girls and eight boys. Eight children (1 female and 7 male) historically had undergone autistic regression. Intravenous immunoglobulin, 200 to 400 mg/kg, was administered every 6 weeks for an intended treatment program of four infusions. In five children, there was no detectable change in behavior during the treatment program. In four children, there was a mild improvement noted in attention span and hyperactivity. In none of these children did the parents feel that the improvement was sufficient to warrant further continuation of the infusions beyond the termination of the program. Only in one child was there a very significant improvement, with almost total amelioration of autistic symptoms over the time period of the four infusions. Once the treatment program was completed, this child gradually deteriorated over a 5-month time period and fully reverted to his previous autistic state. In this treatment program, five children had no response to intravenous immunoglobulin. In the four children who showed mild improvements, those improvements may simply have been due to nonspecific effects of physician intervention and parental expectation (ie, placebo effect). However, in one child there was a very significant amelioration of autistic symptoms. There were no distinguishing historic or laboratory features in this child who improved. Given a positive response rate of only 10% in this study, along with the high economic costs of the immunologic evaluations and the intravenous immunoglobulin treatments, the use of intravenous immunoglobulin to treat autistic children should be undertaken only with great caution, and only under formal research protocols.

Just in this blog, which is amateur and not intended as a rigorous scientific review, we have seen numerous “rare” conditions that lead to “autism” that are actually treatable.

If you add up all these “rare” conditions you get a sizeable proportion of all the autism, diagnosed in those under four years old (i.e. more severe autism).

Clinical Investigations

If you accept that the initial autism diagnosis really tells very little, then you are left, like Hardan, testing all sorts of clever ideas on a trial group of kids who may have one to several, of thousands of discrete dysfunctions (CNVs etc.).

Then if you get a 10% response rate, you are doing great.

If you target something like oxidative stress, that is caused by hundreds of those thousands of discrete dysfunctions (CNVs etc.), then your odds of success shoot up.  This was the case in Hardan’s trial of N-acetyl cysteine.

Hardan is now going to trial oxytocin on kids with autism, but this idea has already been well and truly “trashed” by highly respected mainstream doctors.  They do this because they think autism is something easy to define and measure like high blood pressure.  If it is therapeutic in 10% of cases, that is great.

Quacks, Off-label and Clinical Investigations

I think it is great that Hardan can try all these drugs at Stanford and nobody even thinks of calling him a quack.  The same applies to a small number of inquisitive doctors at Johns Hopkins and Boston Children’s Hospital.

It would be interesting to know how Hardan treats his patients with ASD, who are not enrolled in a clinical trial.  Does he prescribe off-label? 

It is clear that most doctors in developed countries will run a mile/kilometer at the idea of treating somebody off label.  They fear being struck off/sued/ridiculed.

We had the UK pediatrician commenting on this blog that Baclofen was effective in 70+% of her/his patients with anxiety plus Asperger’s, but did not feel happy to continue prescribing it without some supporting evidence from elsewhere.  The fact that it was safe and effective was not enough.

Many of the tiny number of off-label doctors really do look like quacks to me, so I can understand the concern of mainstream doctors not to want to be associated with them.

What is the, scientifically well-briefed, parent supposed to do? (if self-treating is not an option)

I think there should be a way where you can enroll your child in a “clinical investigation”, where you accept that all the treatments are experimental and therefore have a higher level of risk than normal.  You waive your right to sue the doctor, or the hospital.  You can opt out of up to 10% of the therapies, based on valid concern.  For example, you might think IVIG is not safe.

You then enter a program in which all your child’s data can be used for research purposes.  So you agree to have to have EEGs, scans, genetic testing, spinal tap/lumbar puncture, blood tests, urine tests, hair tests etc.

The child is completely profiled and material is stored for possible further analysis later.

All known tests are then carried out, even obscure things like biotin deficiency, creatine deficiency and those amino acids we saw that triggered rare autism.

Then you go through all of the therapies known to be effective in some people.  So it includes memantine, IVIG,  donepezil, bumetanide, oxytocin, propranolol, baclofen, arbaclofen, even Zyrtec, NAC, D-Cycloserine, carnosine, carnitine, pancreatic enzymes, probiotic bacteria  etc.

The whole process would take a year.  If you treated 1,000 children you would then have a wealth of data.

You might have individually rare disorders totaling 15% of cases and then several clusters where the same drugs were effective in sizeable groups of children.  Then you would be able to look back in the data for the biomarkers of each cluster.

Then you would write a smartphone app for doctors to treat autism.  They would input the various biomarkers requested and out would come the suggested drug therapy recommendation(s).  So it would be a “guided off-label” approach where the doctor knows that the recommendations are “scientifically supported” but may not be perfect.

We just need the Simons Foundation to sponsor it! 

If you think it might be too expensive, just remember that at the recent international autism conference in Utah, there were 2,000 scientists and researchers in attendance. What exactly have they achieved, in practical terms, in the last 10 years and are likely to achieve in the next 10 years?

It does seem that some view success as diagnosing ever more people with "autism", so that they can receive "services", when they really should be diagnosing specific biological dysfunctions.

It is not an easy task, but you do not need 2,000 researchers.  You just need 20 pragmatic people to review the data and make a decision tree showing how to choose the 5 drugs most likely to help a particular person, based on their specific biomarkers.  

I guess that would leave 1,980 people with not much to do. 

MitoE, MitoQ and Melatonin as possible therapies for Mitochondrial Dysfunction in Autism. Or Dimebon (Latrepirdine) from Russia?

I did write an earlier post on Melatonin:-

Melatonin for Kids with Autism, and indeed their Parents

Many people with either ADHD or ASD are taking Melatonin to help them sleep better. 

In most countries, other than United Kingdom, Melatonin is available cheaply as a supplement.

This post is about potential therapies for mitochondrial disease/dysfunction.  In this case disease/ dysfunction do not mean the same thing.  Some people appear to have mitochondrial disease of genetic origin that then triggers autistic regression.  Other people with different types of autism, which usually features oxidative stress, appear in various studies to have some mitochondrial dysfunction/abnormalities.  Mitochondria are very important to most aspects of human function.   Impairment of function is associated with many diseases.  In the case of the brain, both Alzheimer’s and Huntington’s disease are associated with mitochondrial dysfunction.

In the case of autism secondary to mitochondrial dysfunction, Dr Richard Kelley from Johns Hopkins has written about his therapy.  He focuses on reducing further oxidative damage and suggests that over time the brain can repair itself.  It was explained here:-

Regressive autism

Other researchers like Chauhan and others on my Deans List, suggest that mitochondrial dysfunction affects non-regressive autism.

So antioxidants that target the mitochondria should be interesting for those with classic early-onset autism.

  

Melatonin

  

Melatonin has 4 main functions:- 

  

Circadian rhythm – regulation of the day-night cycle and hence sleep

Antioxidant

Melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant.  In many less complex life forms, this is its only known function.  Melatonin is an antioxidant that can easily cross cell membranes and the blood–brain barrier. This antioxidant is a direct scavenger of radical oxygen and nitrogen species including OH^•, O^•₂⁻, and NO^•.  Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.  Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also scavengers in what is referred to as the cascade reaction. Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic properties, this means it possesses both hydrophilic (water-loving, polar) and lipophilic (fat-loving) properties.

Immune system

While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. Anti-inflammatory effect seems to be the most relevant and most documented in the literature. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to be the result of melatonin acting on high-affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production, and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.

Metal chelation

In vitro, melatonin can form complexes with cadmium and other metals.

Today’s post is only about the anti-oxidant potential of Melatonin, since that is likely what accounts for to its activity in mitochondria.

Oxidative Stress in Autism

We have seen time and again in this blog that Oxidative Stress is fundamental part of most types of autism. A further study, published three months ago, showed it was present in more than 88% of cases.  So it is about time that people started to treat it, rather than just write about it.

Oxidative Stress in Egyptian Children with Autism: Relation to Autoimmunity

We have reviewed many antioxidants in this blog and it is apparent that there is not a one size fits all solution.  For Monty, aged 11 with ASD, NAC is the best; in other people ALA and/or carnosine have an additional effect.

We saw that Mitochondrial Disease occurring in childhood can present itself as severe regressive autism.  This autism secondary to Mitochondrial Disease is treatable, and once stabilized, symptoms gradually improved.  The therapy is centered on antioxidants to prevent further mitochondrial damage.

Other research has found that mitochondrial damage/dysfunction occurs in the majority of young people with autism, but not adults.  This research is based on analyzing samples from brain banks.

In an earlier post we looked at autophagy and Mitophagy.  This is in effect the cellular spring cleaning that should go on to ensure cellular health.  

Autophagy, Mitophagy, Calpains and mTOR in Autism, but also in aging, cancer, diabetes, Alzheimer's, Parkinson's, and Huntington'setc.

I hypothesize that hyper-activation of calpains, also a feature of Alzheimer’s and Huntingdon’s disease, that leads to altered calcium homeostasis, may exist in autism.  This would explain the excess of intracellular calcium found in autism.  This would cause a decrease in autophagy/mitophagy and might account to the mitochondrial damage seen in brain samples.

All this means that it is worth a second look at oxidative stress in mitochondria in kids whose autism was not regressive.

The good news is that all the research already exists.

There is much recent research into the use of melatonin in autism, for reasons other than sleep.  It seems that at 3X higher than the sleep dose, the other effects become established.  So this would be about 10mg for many children.

There is a French study (MELDOSE)  that has just been completed that looks specifically into the dosage.

Advances in the Research of Melatonin in Autism Spectrum Disorders: Literature Review and New Perspectives

  

Melatonin Dose-effect Relation in Childhood Autism (MELADOSE)

Autism as a disorder of biological and behavioral rhythms: toward new therapeutic perspectives

MitoQ and MitoE

When we looked at antioxidants a while back, it became clear that it is a case of “horses for courses”; meaning that if you want to improve memory one anti-oxidant is best, but it you want to treat an enlarged prostate another is best.

This meant to be an autism blog, but it is sometimes useful to digress.

The antioxidant has to reach its target destination and ideally it should accumulate there.  This means that the concentration is much higher at the target, than in the blood.

The reason why lycopene is great for the prostate, and is chemo-protective there, is that it happens to accumulates there.  The more you take orally the higher the level becomes locally.  Lycopene would be useless to treat mild memory loss, because it cannot cross the blood brain barrier.  So it is cocoa flavonoids for memory loss and lycopene for urinary retention (in males).

When it comes to statin induced myopathy, the official line is that the only effective treatment is to stop using the statin.  However many people find coenzymeQ10 makes mild pains go away.  Statins are known to deplete the body’s own coenzymeQ10 in mitochondria.  Some extra anti-oxidant coenzymeQ10 as a therapy for mild statin induced myopathy, makes perfect sense to me.  It is certainly safe to try.

Statin-induced myopathies

When it comes to diabetic neuropathies, in countries whose medicine is German-based, we have already seen that the antioxidant Alpha Lipoic Acid (ALA) is widely used as an effective drug therapy.  In most Anglo-Saxon countries it is not used as a drug for diabetic neuropathies.  In Dr Kelley’s mitochondrial therapy for regressive autism he uses 10 mg/kg/day of ALA.

EPI-743 is a new drug that is based on vitamin E, another antioxidant.  It is being developed as a therapy for various types of mitochondrial disease, including Rett syndrome.

Edison's orphan drug misses the mark in Phase II

It has been suggested that a very similar product to EPI-743 already exists and is an OTC supplement.  In order to patent a drug it cannot be a natural substance, so I think Edison made something based on vitamin E that was different enough to be patentable.

I have mentioned it somewhere on this blog, I think it is Life Extension Gamma E Tocopherol/ Tocotrienols.

MitoE looks like the perfect vitamin E-based mitochondrial antioxidant.

MitoE  is cleverly made by attaching tocopherol (vitamin E) to a lipophilic cation that can accumulate several hundred-fold within mitochondria due to the negative charge inside mitochondria, delivering tocopherol in a high concentration.

The Mitochondrial Antioxidants MitoE2 and MitoQ10 Increase Mitochondrial Ca2+ Load upon Cell Stimulation by Inhibiting Ca2+ Efflux from the Organelle

Mitochondria-targeted antioxidants in the treatment of disease.

When it comes to the mitochondria we have three interesting choices:-

• MitoQ
• MitoE
• Melatonin

MitoQ  is made by attaching attached ubiquinol (a form of coenzyme Q₁₀.) to a lipophilic cation that accumulate several hundred-fold within mitochondria due to the negative charge inside mitochondria, delivering ubiquinol in high concentrations.

While Dr Kelley uses coenzyme Q₁₀ for autism, the Ubiquinol form is available.  If you believe the advertising, you need much less  Ubiquinol to achieve the same increase in circulating coenzymeQ10.

MitoQ is available as a supplement but at a dosage 90% less than that used in clinical trials.

It is being sold as an anti-aging therapy, the same type of people also use melatonin for the same purpose.

I would think that people with stain induced myopathy that does not respond to Coenzyme Q10 might want to try MitoQ before giving up on their statin.

In some people melatonin seems to lose its effect after a while (feedback loop to the Pineal gland?), the could keep the antioxidant effect in mitochondria by switching to MitoQ.

"When compared to synthetic, mitochondrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a better protector against mitochondrial oxidative stress."

MitoE vs MitoQ vs Melatonin

In the following study they compared the potency of MitoE, MitoQ and melatonin.

Melatonin, which is cheap, did very well

Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organdysfunction in a rat model of acute sepsis

• Oxidative stress and mitochondrial dysfunction are key to the pathophysiology of sepsis.
• The effects of antioxidants targeted to mitochondria on inflammation, oxidative stress, and organ dysfunction were tested in a rat model of acute sepsis.
• Antioxidant treatment reduced mitochondrial damage, sepsis-induced inflammation, and organ dysfunction, a positive finding that should be tested in clinical trials.

MitoQ and MitoE are antioxidants attached to a lipophilic cation that accumulate several hundred-fold within mitochondria due to the negative charge inside mitochondria, delivering ubiquinol or tocopherol, respectively

Melatonin and its main metabolite 6-hydroxymelatonin also reduced cytokine responses, prevented mitochondrial dysfunction, and protected endogenous antioxidants in the same model

We hypothesized that MitoE and melatonin may have a similar beneficial effect in rats treated with LPS and PepG. In this proof-of-concept study, we investigated the effects of treatment with MitoQ, MitoE, or melatonin on biomarkers of organ damage, cytokine responses, oxidative damage, and mitochondrial function after administration of LPS from Escherichia coli plus PepG from Staphylococcus aureus in rats. This model reproducibly creates an inflammatory response, with mitochondrial dysfunction and early changes in organ function also seen in patients with sepsis

Dimebon (Latrepirdine)  

Dimebon is a Russian H1 anti-histamine, like Claritin.  Unlike Claritin it has some very unexpected effects on mitochondria and also NMDA receptors (and others).

A great deal of money was spent (wasted) in the US trying to make the renamed drug, Latrepirdine, into a treatment for Alzheimer’s and Huntington’s disease.  The results in mice looked great and the Stage II trials in Russia looked great, but the phase 3 trials failed.

There is a great deal of data on Dimebon (Latrepirdine) and it has many interesting effects.  It should make the mitochondria work better, be neuroprotective and it should reduce activity at NMDA receptors.

So for a subgroup of people with autism and some mitochondrial dysfunction, this 20 years old antihistamine might be very helpful.

There are claims for it being nootropic, meaning it makes you smarter, but nobody has suggested it for autism.  But then nobody has suggested MitoE or MitoQ for autism either. 

Many antihistamines have secondary actions and we have covered some in this blog like Cyproheptadine.  Rupatadine and Azelastine are H1 antihistamines that are potent mast cell stabilizers.

In the West you can buy Dimebon from the nootropic people, I expect in Russia is it just a cheap 20 year old hay fever pill.

In the recent clinical trials in humans the low dose was 5mg three times a day and the high dose was 20mg  three times a day.   The antihistamine in Russia is produced in 10mg form.

So whereas the OTC MitoQ is 10% of the trial dosage, the standard antihistamine dose Dimebon is similar to the Alzheimer’s trial dose.  From the perspective of safety this is very relevant.

Dimebon (Latrepirdine) enhances mitochondrial function and protects neuronal cells from death

Many antihistamines have secondary effects. Dimebon has numerous:-

Stanford Huntington Project

Coming back to Alzheimer’s it seems, as with cancer, that you can only really expect to halt the disease if you act (very) early or preventatively.  The trials usually take place in people whose brains are already severely compromised.

Failure of Dimebon Raises Questions about Alzheimer’s Trials

To some researchers, the Dimebon failure, and the failure of many other Alzheimer’s drug candidates to date, points to a larger problem:  The treatments are started too late in the course of the disease.

“What you want in such trials are people who are just starting to lose neurons, but typically by the time an Alzheimer’s patient goes to see a neurologist, his or her brain has already been severely damaged,” says Jeffery Kelly, an investigator at the Scripps Research Institute in La Jolla, California, whose work has focused on amyloid-associated conditions. “Considering the way the Alzheimer’s trials are being done now, I’m not sure that even a great drug could be discerned as such.”

  

Why Do All the Large Alzheimer’s Drug Trials Fail?

In response to the continuing negative outcomes of Alzheimer’s clinical trials, researchers have been designing some new trials in which patients are treated earlier in the disease course—when they may respond better—and for periods longer than 18 months, to allow more divergence between treatment and placebo groups. But this “incremental” change in trial designs, as Schneider puts it, still fails to take into account that different drugs have different possible mechanisms of action, different sources of outcome variability, and different possible windows of optimal effectiveness in the disease course. “In principle some drugs could show effects at six months and twelve months while other drugs might not show an effect for a much longer period,”

There are other diseases which feature mitochondrial dysfunction that might benefit more from Dimebon than AD/HD, autism is just one.

 

Conclusion

MitoE and MitoQ are very clever and there are many trials and experiments that have been done using them.  Only MitoQ is available to buy; a 5mg capsule is available OTC.

5mg of MitoQ should have the potency at the mitochondria  of something like 4,000 mg of coenzymeQ10.  The usual “high strength” coenzymeQ10 supplement are 100mg.  Dr Kelley, from Johns Hopkins, suggests 10 mg/kg/day of Coenzyme Q10 for regressive autism, as part of his mitochondria therapy.  So you would think MitoQ should be good for mitochondrial damage in some types of autism.

While MitoQ is quite expensive, melatonin is not.  I wonder why  Dr Kelley does not try/use melatonin.  You can reasonably expect 10 mg of melatonin to have a non-sleep effect.  The drawbacks are that it will send you to sleep and long term use may have an effect on natural melatonin production.

Taking melatonin as a pill should in theory then cause the pineal gland to produce less melatonin.  Over a long period of time this might reduce the body’s capacity to produce its own  melatonin, should you stop giving the pills.  Melatonin is very widely prescribed as drug to treat sleeping problems in ADHD and so you would think any side effects would have been noticed and published by now.  Many kids with autism already receive a lower dose of melatonin to help with sleep. 

Dimebon is in this post, but is not directly comparable to MitoE, MitoQ and Melatonin. 

I rather doubt the OTC MitoQ is potent enough to do much more good than large doses of CoenzymeQ10, which is cheap.

Dimebon is still being researched for Alzheimer’s (see below), even after Pfizer have given up on it.  Autism is not Alzheimer’s or Huntingdon’s, and there are clearly hundreds of variants of autism; but if there is mitochondrial dysfunction of some kind, I cannot see any harm trying these “hay fever pills” for a month.

Latrepirdine improves cognition and arrests progression of neuropathologyin an Alzheimer’s mouse model

In people diagnosed with regressive autism secondary to mitochondrial disease, perhaps just forget Claritin for the summer and buy Dimebon?

Altered Homeostasis in Autism: Cl-, K+, Ca2+, and quite possibly Zn2+

Today’s post will highlight how, perhaps, in 50 years’ time, autism might be understood by the non-scientist.  Sometimes it helps to oversimplify a complex problem in order not to get lost in all the complexities and see what underlying mechanisms may exist.

Homeostasis

Homeostasis is a fancy word for balance or equilibrium.  It is the property of a system in which variables are regulated so that internal conditions remain stable and relatively constant.

All living organisms depend on maintaining a complex set of interacting metabolic chemical reactions. From the simplest unicellular organisms to the most complex plants and animals, internal processes operate to keep the conditions within tight limits to allow these reactions to proceed. Homeostatic processes act at the level of the cell, the tissue, and the organ, as well as for the organism as a whole.

Many diseases involve a disturbance of homeostasis.

Autism is clearly a condition of altered homeostasis, but not severe enough as to become degenerative.

First Chloride Cl^-, Calcium Ca²⁺ , then Potassium K⁺ and now perhaps Zinc Zn²⁺

We have already seen that three very simple ions, chloride Cl^- , calcium Ca²⁺, potassium K⁺ are in the “wrong place” or in the “wrong concentration” in autism.  This in effect tells us that there is altered homeostasis.

Would it then come as a surprise that a fourth ion, zinc Zn²⁺ also appears to be in the “wrong place”, in at least some autism?

Perhaps there is a common mechanism behind this dysfunctional homeostasis? It might be related to cell adhesion molecules like neuroligins (see below), which will be looked at in another post.

Source: By Sarahlobescheese (Created on Paintbrush and Microsoft Word) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Supplementation and Homeostasis

When the lay person hears that something simple is involved in the pathology of autism, the immediate reaction seems to be that you either need more, or less, of it.  So more calcium, more zinc, more magnesium etc.

The problem is more complex; there is enough calcium (and your bones are full of it) but it is not all quite in the right place, so it needs moving around a bit.

When I came across the recent research from Taiwan about the effect of zinc on the NMDA receptors in the brain, I did a quick check and found lots of people supplementing zinc. Some people because the level in their child’s hair was high and some because it was low; the therapy remained the same, more zinc.

Just as Ben-Ari really has figured out many aspects of the excitatory/inhibitory imbalance in GABA in autism and chosen a therapy that indirectly corrects it, the Taiwanese have also gone into their receptor, the NMDA, in detail.  They put forward a well thought out case for modulating it.

Just as Ben Ari choose to move chloride to outside the cells with his drug (Bumetanide), Yi-Ping Hsueh, the Taiwanese researcher, uses an existing  drug called Clioquinol to move zinc from a presynaptic terminal to postsynaptic sites in the brain.  Again, like Ben Ari, she also showed it to be effective in two different mouse models of autism.

Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation

“Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation”

Clioquinolmay help people with autism: study

Scientists compared the interactions of test mice by placing the subjects in a box, mice that had been unchanged, mice with their Tbr1 and Shank2 proteins “knocked off” and another “stranger” mouse.

They found that unchanged mice engaged in high-level interaction with the “stranger” mouse, while mice with Tbr1 and Shank2 deficiencies interacted very little.

Hsueh’s team had previously determined that Tbr1 is a contributing factor of autism, while a team led by South Korean scientist and project coleader Eunjoon Kim discovered that Shank2 is also implicated in the condition.

Both deficiencies hamper the transmission of zinc ions to the NMDAR (N-methyl-D-aspartate) receptor, impairing function.

About 30 percent of children with autism suffer from zinc deficiency.

Hsueh said that previous projects had determined that autism is linked to zinc deficiency, but the research undertaken by Academia Sinica and the South Korean researchers is the first to provide a scientific explanation for the phenomenon by establishing that the social inhibitions caused by autism can be changed by revitalizing the NMDAR receptor.

Hsueh said the results from the experiment conducted on mice can be extrapolated to humans, with a higher than 90 percent relevance between the two species.

She said that as clioquinol is a prescription drug permitted in Taiwan, her team hopes psychiatrists will prescribe the drug to suitable patients.

Zinc Deficiency or Zinc Transmission Deficiency?

A quick review of the research does show very odd levels of zinc in people with autism.  It also transpires that different ways of measuring zinc levels (hair, blood etc) can produce the opposite result.  So it is hard to ascertain that somebody really does have a zinc deficiency.

The key point is the transmission of that Zinc to the NMDA receptors in the brain.  Note the Zn²⁺ modulatory site in the diagram below.

Clioquinol

Clioquinol, has a very tainted past in Japan. The drug was widely used for various conditions in the 1960s, at doses higher than in other countries.  Its use was tied to the emergence of a new condition called Subacute myelo-optico-neuropathy (SMON) , which only seems to have occurred in Japan.

Clioquinol is banned in some countries, but widely available in other countries, like Taiwan,

Clioquinol is showing promise in research into Alzheimer’s.

Some argue that Clioquinol is totally safe and argue for a combined therapy of Clioquinol and zinc.

Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice

Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis Enteropathica

Conclusions

These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

  

SMON: toxicity of clioquinol and the status quo

Subacute myelo-optico-neuropathy (SMON) is a disease characterized by subacute onset of sensory and motor disorders in the lower half of the body and visual impairment preceded by abdominal symptoms. A large number of SMON were observed throughout Japan, and the total number of cases reached nearly 10,000 by 1970. Despite clinical features mimicking infection or multiple sclerosis, SMON was confirmed as being caused by ingestion of clioquinol, an intestinal antibacterial drug, based on extensive epidemiological studies. After the governmental ban on the use of clioquinol in September 1970, there was a dramatic disappearance of new case of SMON. In the 1970s, patients with SMON initiated legal actions against the Government and pharmaceutical companies, and the court ruled that the settlements would be made as health management allowances and lasting medical check-ups. The physical condition of patients with SMON remains severe owing to SMON as well as gerontological complications. The pathological findings in patients with SMON included symmetrical demyelination in the lateral and posterior funiculi of the spinal cord and severe demyelination of the optic nerve in patients with blindness. Although clioquinol may show activity against Alzheimer's disease or malignancy, its toxic effects cause severe irreversible neurological sequelae. Thus, caution must be exercised in the clinical use of clioquinol

Zinc Effects on NMDA Receptor Gating Kinetics

Zinc is an essential micronutrient that accumulates in brain and is required for normal development and function. Both deficiency and excess of zinc alter behavior and can cause brain abnormalities and neuropathies, of which epilepsy, ischemia, and Alzheimer’s degeneration have been the most studied. Aside from catalytic and structural functions in many proteins, ionic zinc (Zn2+) may play important roles in neurotransmission. Free Zn2+ accumulates in the synaptic vesicles of a specific subset of glutamatergic neurons and is coreleased with glutamate in an activity-dependent manner. Upon release, free Zn2+ may modulate neurotransmitter receptors and transporters, activate zinc-sensing metabotropic receptors, and/or gain cellular access through Ca2+-permeable channels. At certain glutamatergic synapses, a primary role for vesicular zinc is to reduce N-methyl-D-aspartate (NMDA) receptor currents . A wide range of extracellular Zn2+ concentrations directly and specifically inhibit NMDA receptor responses, and in the hippocampus, a region highly enriched in vesicular zinc, zinc-positive glutamatergic synapses are also enriched in NMDA receptors. The inhibitory effects of Zn2+ on NMDA receptors have received considerable attention due in part to the pivotal role played by these receptors in synaptic transmission and plasticity. Still, the mechanism by which the inhibition occurs is incompletely understood.

Other ways of modifying NDMA receptors

As the excellent recent paper below from Korea points out, “correcting NMDAR dysfunction has therapeutic potential for ASDs”.  The problem is that in some autism there is too much NMDAR function, and in others there is too little.

So we should not expect much success from any “one size fits all” therapy.

NMDA receptor dysfunction in autism spectrum disorders.

Abnormalities and imbalances in neuronal excitatory and inhibitory synapses have been implicated in diverse neuropsychiatric disorders including autism spectrum disorders (ASDs). Increasing evidence indicates that dysfunction of NMDA receptors (NMDARs) at excitatory synapses is associated with ASDs. In support of this, human ASD-associated genetic variations are found in genes encoding NMDAR subunits. Pharmacological enhancement or suppression of NMDAR function ameliorates ASD symptoms in humans. Animal models of ASD display bidirectional NMDAR dysfunction, and correcting this deficit rescues ASD-like behaviors. These findings suggest that deviation of NMDAR function in either direction contributes to the development of ASDs, and that correcting NMDAR dysfunction has therapeutic potential for ASDs.

Pharmacological modulation of NMDAR function can improve ASD symptoms. D-cycloserine (DCS), an NMDAR agonist, significantly ameliorates social withdrawal  and repetitive behavior  in individuals with ASD.

These results suggest that reduced NMDAR function may contribute to the development of ASDs in humans. Elevated NMDAR function is also implicated in ASDs. Memantine, an NMDAR antagonist, and its analogue amantadine improve ASD-related symptoms including social deficits, inappropriate language, stereotypy, cognitive impairments, lethargy, irritability, inattention, and these results, together with the DCS results, highlight the importance of a normal range of NMDAR function, and suggest that deviation of NMDAR function in either direction leads to ASD.  This concept is in line with the emerging view that synaptic function within a normal range is important and its deviation causes ASDs and intellectual disability

Mice lacking neuroligin-1, an excitatory postsynaptic adhesion molecule, show reduced NMDAR function in the hippocampus and striatum, as evidenced by a decrease in NMDA/AMPA ratio and long-term potentiation (LTP) Neuroligin-1 is thought to enhance synaptic NMDAR function, by

directly interacting with and promoting synaptic localization of NMDARs.

CDPPB, a positive allosteric modulator of mGluR5 that potentiates similarly normalizes NMDAR Dysfunction and behavioral deficits, consistent with the idea that indirectly modulating NMDARs through mGluR5 is a viable approach for treating ASDs.

ASDs involve diverse core and comorbid symptoms. Consistent with this, a single autism-related mutation, neuroligin-3 R451C, causes diverse synaptic phenotypes in different brain regions and circuits. Therefore, synaptic changes should be analyzed in greater detail, ideally using brain region-specific and cell type-specific conditional gene ablation, as recently reported.

Modulators of mGluR5, in addition to NMDARs and AMPARs, have been considered to be a new means of regulating glutamatergic transmission. Therefore, pharmacological rescue of animal models of ASD should ideally involve modulation of both NMDARs and mGluR5, or even other NMDA-modulatory approaches, to better facilitate translation to clinical therapy.

Lastly, because our hypothesis associates bidirectional NMDAR dysfunction with ASDs, there may be clinical cases, such as where individuals with reduced NMDAR function are treated with NMDAR antagonists, which might aggravate the situation and affect the interpretation.

None of the existing autism therapies that modify NDMA receptors have been uniform knockout successes, but are effective in some cases.

These include:-

·        Memantine an NMDAR antagonist

·        D-Cycloserine an NMDAR agonist (the opposite of Memantine)

·        Ketamine, an NMDAR antagonist

Intranasal Ketamine Treatment in an Adult With Autism Spectrum Disorder

So if you respond to Memantine, the chances are you would benefit from intranasal ketamine;  but D-Cycloserine would make you worse.

They recently terminated early the large Memantine autism trial.  In a rational world they would try D-Cycloserine on all those kids who failed to respond to Memantine.  We do not live in a rational world.

Conclusion

I have a feeling that several dysfunctions in autism, including the E/I imbalance of GABA, will ultimately be traced back to neuroligins.

This is an area of science in its infancy and so for today we have to treat the consequences individually. 

Fortunately, the Simons Foundation is funding the right people and so, in the end, we will get to the bottom of it all.

Function and dysfunction of neuroligins

I hope the Taiwanese test Clioquinol on some humans with ASD and let us know the results.  

As the clever Korean researcher above has highlighted, Clioquinol will only benefit those with reduced NMDAR function.  So if I have got things the right way round, Clioquinol will help the same group that respond to D-Cycloserine.  The others would need Memantine/Ketamine, or even better, they have perfect NMDAR function and need nothing at all.