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.

Bumetanide “reverses” MR/ID in Down Syndrome

You probably know what Down Syndrome looks like, but you probably never expected the above life expectancy data.  It used to be the case that kids with this disorder were institutionalized after birth.

Source:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445685/figure/F2/

In an earlier post I suggested that some types of Mental Retardation (MR)/Intellectual Disability (ID) should be treatable.  I was thinking about RASopathies, dendritic spine morphology and the GABA E/I (Excitatory/Inhibitory) imbalance found in autism.  I even suggested to the autism researchers working on the bumetanide approval process that the simplest measure of effectiveness would be to measure IQ before and after treatment.

Recent research has shown that in Down Syndrome GABA is also excitatory.  GABA should be inhibitory, otherwise the brain cannot function properly and there will be a large risk of seizures.  In many people with autism GABA is excitatory; this reduces their cognitive function and leads to almost 80% having unusual epileptiform activity (like “pre-epilepsy”) and about 35% going on to developing seizures.

In the Down Syndrome mouse model the researchers found that Bumetanide improved cognitive function, via the shifting of GABA from excitatory to inhibitory.

Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.

I thought that was great news.  Perhaps other types of MR/ID are also the result of GABA E/I imbalance, they too would be treatable with Bumetanide.

The question remains, does anyone care enough to bother about these people?  Take a look at the life expectancy chart at the top of this post.  Things have got much better, but there is a long way to go.

Down Syndrome

Most people have heard about Down Syndrome (DS) and I certainly knew more about what DS looked like than what autism looked like.

People with DS look different, are short, and 99% have some degree of MR/ID.  About 10% also have autism and half will develop epilepsy.

Down syndrome is caused by having three copies of the genes on chromosome 21, rather than the usual two.  The extra genetic material present in DS results in overexpression of a portion of the 310 genes located on chromosome 21. This overexpression has been estimated at around 50%.

Some adults with DS lose the ability to use speech when they are about 30 years old.

Until 1970 children with DS used to live for just 10 years, whereas today most survive into their 50s.

About 92% of pregnancies in Europe with a diagnosis of Down Syndrome are terminated. In the United States, termination rates are around 67%.  When non-pregnant people are asked if they would have a termination if their fetus tested positive only 23–33% said yes.

Reversing excitatory GABA_AR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome

Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl⁻-permeable GABA_A receptors (GABA_ARs) contributes considerably to learning and memory deficits in DS mouse models. However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here GABA_AR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABA_AR-driven Cl⁻ currents (E_Cl) was shifted toward more positive potentials in the hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation Cl⁻ cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored E_Cl, synaptic plasticity and hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.

Conclusion

It would appear that excitatory GABA may be more common than anyone thought.  I wonder how many other people with MR/ID might be affected and be potential beneficiaries of this very inexpensive therapy.

I did ask one of my doctor relatives if she has any patients with DS; I said that there may be a treatment for their MR/ID.  She is not going to prescribe her patients anything off-label, so unless Ben-Ari decides he wants to help people with DS, as well as ASD, people will DS will remain untreated.  I will ask him.

Also, given the large amount of money going into the genetics of autism, perhaps it would be worth looking at those 310 genes located on chromosome 21 to see if the overexpression of one may trigger speech loss in people with regressive autism and/or might be present from birth in people with classic autism.  One of them must trigger the speech loss in that sub-group of adults with DS.

End of School Year

As another school year comes to an end it was time for Monty, aged 11 with ASD,’s end of year grades and the parent teacher meeting.  Monty attends a small mainstream international school with his own assistant.

This year is particularly interesting because we have the same class teacher, Miss B, this year that we had three years ago (prior to starting to develop Monty’s autism Polypill).  So if anyone can judge the impact, it should be her.

In the English system Year 4, is where you find 8-9 year old typical kids and equates to 3^rd grade in the US system.  Monty just finished Year 4.

After completing Year 3 first time round with Miss B three years ago, with a traumatic several months of aggression and cognitive and behavioral regression, we put Monty to start Year 2 again.  At the end of the first term in Year 2 (second time around) he started Bumetanide.

Year 1

Year 2

Year 3            Miss B

Year 2            (repeated)

Year 3            (repeated)

Year 4            Miss B again (current year now ending)

Year 5            Next school year starting Sep 2015

First time around with Miss B, Monty could not really follow any instruction from her and he was entirely dependent on his 1:1 assistant.  

At home, in the afternoons and holidays, he had learned to speak, read and write using ABA.  At school he was assessed on simple tasks like being able to change into his indoor shoes independently, or with prompting.  Academic assessment was all customized for him; no attempt was made to use the same assessments as his classmates.  Assessment was extremely basic, like adding one to a single figure number.

Some children are diagnosed very young with autism and by five years old things have changed so much that they have lost their diagnosis.  Monty is not one of those.  He was diagnosed at three and a half and continued to get more autistic.  Using PECS and ABA he gained basic speech.  With 40 hours a week of 1:1 assistance he learned to read and write, but we did not even try and teach numeracy.

We were following the standard trajectory of classic autism; no learning followed by (very) slow learning.

This distorted learning trajectory is one reason why I feel that Asperger's should remain entirely separate from classic autism; calling them both "autism" does justice to neither.  In Asperger's there is no language delay and no impaired cognitive function, resulting in quite different people, with very different issues.  I am beginning to feel that when you treat classic autism, as far as you can, the result will be something not dissimilar to Asperger's. What happens if you treat Asperger's?

After initiating pharmacological therapy, we now have had nearly three years of skill acquisition at a rate similar to a typical child, of average IQ.

So Monty finished Years 2, 3 and 4, had the same assessment as the NT classmates and is not at the bottom of the class of 12 kids, in any subject.  Monty is certainly not a “straight-As” student, like his big brother is; he is now more of a C student with some Bs.  But as I told his teacher Miss B, the great achievement is that we are even discussing the results of standard assessments at all.

Pleiotropic effects?

Sometimes drugs seem to have broader beneficial effects than intended, these get called pleiotropic effects.

It looks very likely that one or more elements in Monty’s Polypill have some pleiotropic effects, or some synergistic effects.  

There is a study showing the effect of ten months of Bumetanide treatment.

Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study

My feeling after 30 months of Bumetanide treatment is that it provides a critical step-change in cognitive function.  Following this one-time gain, things seemed to progress faster cognitively only when other elements were added.

The following papers on pleiotropic effects of drugs in the PolyPill do not refer to autism, but are interesting.eiotropic Effects

PLof

Pleiotropic effects of calcium channel blockers

PLEIOTROPIC EFFECTS OF STATINS

N-acetyl-cysteine pleiotropic effects

  

Future progress

As I told the teacher,Miss B, a good plan seems to be to just keep following the regular kids and keep going until the end of year assessment might put Monty at the bottom of the class.  Should that happen, we can just repeat that year again.

This is not the advice you will likely find anywhere else regarding educating a boy with classic autism in a mainstream classroom.  Indeed it is pretty clear that in mainstream schools “inclusion” just means a class within a class; so the child with autism and his assistant are doing one activity, while the class teacher and the other kids do something entirely different.