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Showing posts with label mitochondria. Show all posts
Showing posts with label mitochondria. Show all posts

Tuesday 8 March 2016

Meldonium/Mildronate for Athletic Performance, but seemingly also for Mitochondria, Neuroinflammation, Cognition and Alzheimer’s





What you see is what you get,
not what you see is what he took.



Today’s post is another very short one.

You may have seen that Maria Sharapova, the tennis player has got into trouble for taking a Latvian drug called Meldonium/Mildronate for the last decade.


Like many people, I did a quick check on this drug to see what it does and if you could innocently not know that it is performance enhancing.  Well it does lots of performance enhancing things like increasing blood flow and increasing your capacity to exercise.


What drew my attention was its effect on mitochondria, cognition and even as a potential Alzheimer’s Therapy.

I should point out that Bumetanide, the most effective Autism therapy my son uses, is also a banned substance under the World Doping Agency rules.  Bumetanide and other diuretics are used as masking agents by athletes taking performance enhancing drugs.  


Mildronate

Mildronate is a Latvian drug, widely prescribed across the former Soviet Union.

For people with autism who respond to carnitine therapy, or with a diagnosed mitochondrial disorder it looks very interesting.  There really are no approved treatments that reverse such disorders, just to stop them getting worse.

Mildronate also shows some promise for both Parkinson’s and Alzheimer’s disease in animal models.


Mildronate improves cognition and reduces amyloid-β pathology in transgenic Alzheimer's disease mice

 

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP(SweDI)). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid-β deposition in the hippocampus, increased expression of the microglia marker Iba-1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP-43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid-β pathology in a mouse model of AD and its possible therapeutic utility as a disease-modifying drug in AD patients.





This review for the first time summarizes the data obtained in the neuropharmacological studies of mildronate, a drug previously known as a cardioprotective agent. In different animal models of neurotoxicity and neurodegenerative diseases, we demonstrated its neuroprotecting activity. By the use of immunohistochemical methods and Western blot analysis, as well as some selected behavioral tests, the new mechanisms of mildronate have been demonstrated: a regulatory effect on mitochondrial processes and on the expression of nerve cell proteins, which are involved in cell survival, functioning, and inflammation processes. Particular attention is paid to the capability of mildronate to stimulate learning and memory and to the expression of neuronal proteins involved in synaptic plasticity and adult neurogenesis. These properties can be useful in neurological practice to protect and treat neurological disorders, particularly those associated with neurodegeneration and a decline in cognitive functions.

The obtained data give a new insight into the influence of mildronate on the central nervous system. This drug shows beneficial effects in the regulation of cell processes necessary for cell integrity and survival, particularly by targeting mitochondria and by stabilizing the expression of proteins involved in neuroinflammation and neuroregeneration. These properties can be useful in neurological practice to protect and treat neurological disorders, such as Parkinson’s disease, diabetic neuropathies, and ischemic stroke. Moreover, because mildronate improves learning and memory, one may suggest mildronate as a multitargeted neuroprotective/ neurorestorative drug with its therapeutic utility as a memory enhancer in cognitive impairment conditions, such as neurodegenerative diseases, schizophrenia, and other pathologies associated with a decline in awareness.



Mildronate, a representative of the aza-butyrobetaine class of drugs with proven cardioprotective efficacy, was recently found to prevent dysfunction of complex I in rat liver mitochondria. The present study demonstrates that mildronate also acts as a neuroprotective agent. In a mouse model of azidothymidine (anti-HIV drug) neurotoxicity, mildronate reduced the azidothymidine-induced alterations in mouse brain tissue: it normalized the increase in caspase-3, cellular apoptosis susceptibility protein (CAS) and iNOS expression assessed by quantitative and semi-quantitative analysis. Mildronate also normalized the changes in cytochrome c oxidase (COX) expression, reduced the expression of glial fibrillary acidic protein (GFAP) and cellular infiltration. The present results show that the neuroprotective action of mildronate results at least partially from anti-neurodegenerative (anti-apoptotic) and anti-inflammatory mechanisms. It might be suggested that the molecular conformation of mildronate can facilitate its easy binding to mitochondria, and regulate the expression of different signal molecules, hence maintaining cellular signaling and survival.



Conclusion

If any of the Russian readers of this blog have trialed Mildronate in their child with autism secondary to mitochondrial disease (AMD), please let us know the result.


Perhaps Dr Kelley should try mildronate, it clearly falls into his area of interest.




Sunday 17 January 2016

Autism PolyPill vs Personalized Medicine and the KD/MAD diet




The idea behind personalized medicine is the realization that humans are all slightly different and that some of the diseases they suffer, like autism, are also all slightly different.  In order to treat them optimally, you would need to use drugs and dosages customized to each person.





Here below are three slides used to illustrate Personalized Medicine in cancer care.  Instead of treating “cancer”, four sub-types are identified and then treated using four different drugs.  Each person only receiving the effective drug.













Autism is not cancer, but understanding cancer gives you a much better concept of what can underlie a highly complex disease like autism.  You need to consider multiple hits as in cancer, which is very similar to Russian Roulette.

The thing that does not seem to exist in cancer is the "double tap", when in a minority of cases, a moderate case sudden changes to a severe case.  This is caused by a new factor coming into play, or an existing factor that had been dormant. In cancer, metastasis is a progression of the existing condition, not something unrelated.  

In the above case there were just for four types of cancer and all you have to so is to find the molecular biomarker for each one.  Then you treat each person with the appropriate drug and avoid side effects from the wrong drugs.

Autism is much more complex because it has "layers" and these may change over time. You have to treat the outer layer first.  This explains why some effective autism treatments appear to "stop working".  Something else has started to work and now forms the outer layer.  This could be related to mast cells, mitochondrial dysfunction or probably a whole host of other factors.

The autism equivalent graphic above, would have people in multiple colours as if dressed.  Just as people change the colour of their clothes, some of the colours of each figure might vary over time and this is what really complicates things.

People with oxidative stress might be represented by having blue socks, reductive stress red socks and "no" stress black socks. There would be lots of blue socks and very few of red or black socks.

NAC for those with blue socks.




PolyPill

So my idea of a PolyPill arose from the idea that when a non-verbal three year old with some odd behaviors goes to his doctor, he might not come home empty handed, and not with those wholly inappropriate psychiatric drugs.  The PolyPill might contain some ingredients that were not necessary, but it would show that a single pill could produce marked improvements in the majority of cases.  All without any complicated and expensive genetic or metabolic testing.

Since I only treat one person, my PolyPill is really a perfect example of personalized medicine.  As time passes, it becomes even more tailor-made.

Monty’s big brother did recently ask why don’t you actually make the PolyPill?  Good question. I did look into this in some detail and even gave a presentation to the European drug regulator (EMA).  There are enormous barriers, few of which relate to developing the drug itself.

If I was James Simons (of the Simons Foundation) that is exactly what I would do, make a PolyPill that could help hundreds of thousands of people.  But unless I receive a call from them, I’ll be sticking with a personalized medicine called Monty’s PolyPill.

The huge advantage of Personalized Medicine is that it minimizes the number of drugs and quasi-drugs that you give.  Let's not pretend that nutraceuticals and OTC supplements are not drugs. This is a concern raised on this blog, just how many ingredients can you (safely) have?  

It certainly can be a bother dispensing them.  Your typical multivitamin contains 14+ ingredients, who would give their child 14 pills at breakfast?  Almost nobody.  But a single little multivitamin pill is just fine. Do they even need all 14?  Unlikely.



So, how many drugs can a PolyPill have?

That was Agnieszka's point in a recent comment.  Things do interact and this does include supplements as well as drugs.  It can be time consuming preparing all these ingredients, not to mention having to swallow them.

This is why someone took Dr Kelley's mitochondrial therapy and packaged it up and sell it as a single product, Mitospectra.




DAN! and Diets over Time

Another vaguely related issue is what happens to autism therapies over time.

It is clear that while allergies may moderate over time and hormonal changes have secondary effects, the core dysfunctions in autism are likely to be permanent.  You can treat them, but you probably cannot cure them.  None of my therapies seem to be disease changing.

So what happens to the thousands of kids, mainly in the US, who follow DAN therapies and diets?  This was raised recently on a popular autism blog and the conclusion was that, after a few years, the great majority of people give up.

This is rather sad.  It shows that the majority of those therapies had no significant effect on the majority of people that tried them, otherwise they would not have given up.

An example being the blog author, with one of those children who had a "second tap", that shifted him to the very severe kind of autism.  This became a new "outer layer", in Peter-speak.  What if that second tap was due to mitochondrial dysfunction (as appears to be relatively common)?  If that was the case, it is not surprising that the gluten free diet did not help, nor  HBOT etc.  Surprisingly, there actually is a diet that might have helped.  No, not the GAPS diet, but the Ketogenic Diet (KD); more a medical therapy than a diet, so well worth reading about.

I was surprised how much evidence there is that indicates that the Ketogenic Diet (and hence likely also the Modified Atkins Diet, MAD) MIGHT  help those with mitochondrial disease. There is no reason to think unrelated diets would do any good whatsoever.

In some cases the Ketogenic Diet can have disease changing effects, meaning you do not need to stay on it for life.  Many people transfer to the MAD.

So if you have a case of severe autism, resulting from a second tap, or a late regression, and nothing covered in this blog seems to help, test for mitochondrial disease.  

If Dr Kelley's therapies reverse the decline, but progress is painfully slow thereafter, it could be worth trying the KD or MAD.








Sunday 8 November 2015

The Brain is Hypothermic in Mitochondrial Disease, but is it in Autism?


Having noted in the previous post something as simple, and measurable, as reduced blood flow in the brain exists in autism, I decided to dig a little deeper.

Not only can you measure blood flow in specific regions of the brain, but using Magnetic Resonance Spectroscopy you can measure the temperature of the brain.

Intense heat production is an essential feature of normal brain energetics; most of the energy used for brain functioning is eventually released as heat.  In the brain, heat is produced mostly by mitochondrial oxidative chemical reactions. Most of the energy required for brain activity is generated from the net chemical reaction of oxygen and glucose; some of this energy (33%) is immediately dissipated into heat, and the rest (67%) is used to synthesize ATP. The final ATP hydrolysis releases part of the energy back to the system as heat.

Note that your core temperature is not the same as your brain temperature.


Brain temperature Tbr should be near constant

Increases in Cerebral Blood Flow reduce Tbr and increases in brain metabolism increase Tbr.

Neuronal activity is temperature dependent, with neuronal firing increasing with increased temperature.  Many other functions in the brain are temperature dependent.

When your brain gets too hot febrile seizures can be the result, caused by excessive neuronal firing.


Mitochondrial Disease

Since heat in the brain is produced mostly by mitochondrial oxidative chemical reactions, when mitochondrial disease is present, it would be expected that there would be less heat and therefore a lower Brain temperature Tbr.  This time biology is indeed logical and this is the case.  People with mitochondrial disease have measurably colder brains.




We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.


The question is whether this lower brain temperature, in itself, leads to changes in brain function/performance and hence mood, behaviours and cognition.



Mitochondrial Disease in Autism

There are various types of mitochondrial disorder in autism and, confusingly, different terminology is used for similar biological conditions.  Regressive autism triggered by a viral illness, fever, or in some cases a reaction to a vaccine is likely mitochondria-related.

I have covered Dr Kelley from Johns Hopkins ideas on this subject, but there are others.  Here are some other perspectives:-







Fever Effect in Autism

It is well documented that in many people with autism their symptoms subside when they are sick and have a fever.  This is the so-called “fever effect”.  It only applies to some people with autism and in a small number the effect can be dramatic.

There are numerous unproven theories.









  


Background:  The observation that some ASD patients manifest clinical improvement in response to fever suggests that symptoms may be modulated by immune-inflammatory factors.  The febrile hypothesis of ASD stems from this observation, and could be due to (1) the direct effect of temperature; (2) a resulting change in the immune inflammatory system function associated with the infection of fever; and/or (3) an increase in the functionality of a previously dysfunctional locus coeruleus-noradrenergic (LC-NA) system.  
Objectives:  To assess the effect of hyperthermia on ASD symptoms.
Methods:  We completed a double blind crossover study of 15 children with ASD (5 to 17 years) using two treatment conditions, hyperthermia condition (102°F) and control condition (98°F) in a HydroWorx aquatic therapy pool.  Five children with ASD without fever response acted as controls, completing only the hyperthermia condition, to ensure safety and feasibility.  Safety measures and Social Responsiveness Scale (SRS) were collected.  Ten patients with ASD and history of fever response were enrolled and received both treatment conditions.  Vital signs, temperature monitoring and clinical observations were completed throughout their time in the pool.  Parents completed the SRS and RBS-R.  Pupillometry biomarker and buccal swabs for DNA and RNA extraction were collected pre and post pool entry. 
Results:  Ten subjects with ASD and a history of fever response were enrolled and completed the hyperthermia condition (102°F) and control condition (98°F) at the aquatic therapy pool.  Improvement during the hyperthermia condition (102°F) was observed in social cognition, using the Social Responsiveness Scale (SRS) total raw score (p = 0.0430) and the SRS Social Behavior subscale raw scores (p = 0.0750); repetitive behaviors, using the Repetitive Behavior Scale-Revised (RBS; p =0.0603) and the SRS Restricted and Repetitive Behavior subscale (p = 0.0146); and on global improvement, using the Clinical Global Impression Scale-Improvement (CGI-I; p=0.0070). 
Conclusions:  This study demonstrates the feasibility of observing the direct effect of temperature in children with ASD, both with and without a history of febrile response, and provides preliminary data on the relationship between body temperature and changes in social and behavioral measures. It explores the direct effects of temperature on ASD symptoms, and offers a window into understanding mechanisms involved in improvement in ASD symptoms during fever episodes.  Behavior changes observed for each child were similar to those observed by parents during febrile episodes, including increased cooperation, communication and social reciprocity and decreased hyperactivity and inappropriate vocalizations. This study is important for the development of translational models on the mechanism of symptom improvement and the identification of novel targets for therapeutic development.



Why not measure Brain temperature Tbr in a large number of people with Autism?

The above study at the “Albert Einstein” medical school involved putting people in hot tubs to warm them up and then measuring their autistic symptoms. You would have thought it would have occurred to them to quickly pop upstairs to the MRI to measure brain temperature Tbr.  I do not think you need to be an Einstein to think of that.

Perhaps the people that exhibit the fever effect are the ones with low brain temperature Tbr ?  That would seem well worth checking.

It also is logical to just warm up the part of the body that will affect behaviour.


Hypothermia in Mouse Models

If you look up hypothermia and autism you again encounter Robert Naviaux, from University of California San Diego, and not much else.  Naviaux is a very clever researcher, but more importantly he just does not give up.  He is doggedly pursuing his antipurinergic therapy for autism.

It turns out that hypothermia is a feature of the maternal immune activation (MIA) mouse model of autism that he is using in his research.

Indeed his antipurinergic therapy corrects this hypothermia.








From:-


Relative hypothermia is a long-term feature of the Poly(IC) MIA Model. This is the lower line (PICSAL), when treated with Suramin, you get the yellow line PICSUR, with a higher body temperature similar to that of the regular mice (blue lines)  When they gave Suramin to regular mice (dark blue line) the was no overall change in body temperature.

So we know that in at least one major mouse model of autism, hypothermia is known feature.  Did anyone measure it in the others?



Conclusion

If raising Tbr improves autism symptoms so much, in some people, then why not just figure out a clever way to increase it?

Raising blood flow apparently should lower Tbr.

There are likely numerous options like increasing the oxygen level in the blood, which might be expected to increase heat production, for example using Diamox (Acetazolamid). 

Reducing heat loss by wearing a wooly hat, should marginally raise brain temperature, unless the brain then compensates for this.

Since the illicit drug MDMA, or ecstasy, is already known to raise brain temperature, there probably are ways to develop a safe drug therapy to achieve a small increase in brain temperature.  
  

Hopefully Naviaux will find a safe antipurinergic therapy, which might also be used in people with low Tbr, as well as broader autism.




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?