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Monday, 29 June 2015

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:-



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:-



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, O2, 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.



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.  



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.



  





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.



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.



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.








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




  • 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.




Many antihistamines have secondary effects. Dimebon has numerous:-














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.




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.”


  


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.



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











16 comments:

  1. Hi, I couldnt google the results of the MELADOSE French study. Can you kindly post the link if you have it.

    Thanks,
    Mahesh

    ReplyDelete
    Replies
    1. Hi Mahesh, I do not have the study, perhaps it has not het been published. The lead researcher, Tordjman, is also the author of the third paper I listed in the above post. That paper is from february 2015, it does list all the published studies on melatonin.

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  2. My understanding is that melatonin is a terminal antioxidant with no known feedback loop. Notwithstanding that, I think it is a good idea to do periodic on/off dosing just in case. Had emailed Tordjman last year about the MELADOSE study and they were still doing statistical analysis at that time. Hopefully it is published soon. I predict there is efficacy here in a dose dependent manner, but challenge is very short half life of melatonin, so any benefit is mostly gone by the morning.

    ReplyDelete
  3. We already use melatonin for sleep. For my son I stopped with the minimum effective dose to have him sleeping decently, but he can tolerate larger doses, so it should be no problem to run a little try-out.
    On the other hand, I myself have HUGE headaches if I take more than 3 mg, so beware.

    Thanks for the info on MitoQ and MitoE. I have a hard time giving him the correct dose of Q10 (he doesn't like the taste), so these may work as alternative.

    About Dimebon, we have our share of allergies here, and anti-histamine is a must in our home...so yeah, why not?

    Piracetam is another nootropic said to be protective of/beneficial to mitochondria. I haven't tried for my kid yet, but the more I research the more interesting it seems.

    Jane.

    ReplyDelete
    Replies
    1. Some people actually use melatonin to treat headaches, so we are all different. Piracetam is interesting and free of side effects. Some people respond very well to Piracetam, but for others it does nothing. There are numerous proposed modes of action.

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  4. Hello Peter, I have just read this and your later posts of this summer, so full of really fascinating analysis which I am eager to study further and potentially explore. In the meantime I am writing to see what your thoughts are on the study just released yesterday August 4 on the MOCOS gene - and the write up indicating it could tie together the GI and communication-lag difficulties so frequently seen in autism? It was a French research paper and was reported on SFARI as well as elsewhere - Kind regards, Mira

    ReplyDelete
    Replies
    1. Hello Mira, that French paper is really excellent. It links many things together from oxidative stress to purinergic signaling. The latter is the focus of Dr Naviaux at the University of California (see below)

      http://www.nature.com/tp/journal/v4/n6/full/tp201433a.html

      The French paper did not seem to mention that a corrective therapy already exists, although it seems to have been used only once and it was for rescue of lethal molybdenum cofactor deficiency, which would seem to be an extreme version of what the French identified.

      http://hmg.oxfordjournals.org/content/13/12/1249.long

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    2. Thanks so much for those further links. I thought I should tell you we trialed the Bumetanide for a month this summer. Then we went off to see if there is a difference - conclusion, not sure. We will try it again in the fall after other August therapies are concluded. This is a great blog that benefits many parents, thanks, Mira

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    3. Bumetanide only works in some people (with over expression of NKCC1 in the brain) so it may well be that your child does not have this issue. In people who respond there is a big change, which you would not miss. I think about half of people seem to respond, but the researchers think it is more. They suggest trying for two months.

      Delete
  5. Hi Peter! How are you? I have just bought Choline & Inositol by NOW and i've ordered Piracetam as well for my 13-year-old son who has Tourettes and ASD. He has been suffering a lot all these years and i'm willing to try everything to help him. I've read that Piracetam could also ameliorate the symptoms of Tourettes and of course give that cognitive boost that our children lack.What i wanted to know is the dosage of Piracetam and Choline that i should give. I've done some researching but i 'm confused! Our doctor seems to consider all these stuff nonsense and wants me to stick to Risperdal so i don't want to ask him about the dosage. My son weighs 80 kg. I would really appreciate it if you could help me!
    Georgia

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    Replies
    1. Based on what I have read, people the size of your son would be taking 2 to 4g a day, but some take much more.

      In my son the big cognitive boost came from bumetanide, it had a much bigger effect than piracetam. It all depends what type of autism it is and how severe it is

      Piracetam is seen as very safe, so it is worth a try. In some people choline increases the effect. In some people just choline has a good effect, in others choline has a bad effect. It is a case of trial and error.

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    2. Thanks for the information! As far as Bumetanide is concerned, is it safe to give it to a child without having a doctor monitoring the heart? Are there any prior medical check-ups one should do before starting taking it?

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    3. Bumetanide is given to babies, so your son should be fine. It is necessary to check potassium levels in the blood. This is a standard blood test. About 20 percent of people need to take a potassium supplement to replace what is lost in urine. This is all very easy and well worth it. I was advised to wait two weeks and then check potassium. Before the two weeks was up it was clear that the drug was effective, potassium level was fine. I have given bumetanide for two and a half years and have seen a vast step forward in cognitive skills. In the ideal world you would measure potassium before starting, it depends how easy taking blood is. We did not check before and have only checked it three times since, because levels were normal and I do give a daily potassium regardless.

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  6. Hi Peter, have you heard about Elysium Health and its base product? Might be a fad, but they sure got a credible set of people behind, with several Nobel laureates for such a simple supplement. I intend to try the combo of nicotinamide riboside and pterostilbene myself in the future, as allegedly it might help mitochondrial dysfunction.

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    Replies
    1. It is interesting. Nicotinamide riboside, looks like it should also be sold to treat obesity. There are several suppliers.

      I think it is a case of trial and error to see what works. What costs most may not be the most effective.

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