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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.




16 comments:

  1. Peter, do you have any thoughts on the most bioavailable brand or type of turmeric.
    Thank you.

    ReplyDelete
    Replies
    1. I have not used turmeric or its most active ingredient curcumin. One reader found the Longvida version of curcumin very helpful. Another reader pointed out that there are potentially beneficial substances in turmeric other than curcumin.

      I bought some longvida curcumin and will be trying it.

      Delete
  2. My husband suffers from a cognitive impairment due to a Diffuse Axional Traumatic Brain Injury. Specifically to his front lobe. Has anyone tried this medicine for treatments on TBIs?

    ReplyDelete
    Replies
    1. Two therapies mentioned elsewhere on this blog have been shown to improve recovery after TBI. One is high doses of a statin like Atorvastatin and the other is the hormone progesterone. It is best to use immediately after the TBI, but should still help afterwards.

      Neuroprotective Strategies for Traumatic Brain Injury: Improving Clinical Translation
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907865/

      Delete
    2. I would also add low level laser therapy to that list as potentially very beneficial in TBI.

      There are quite a few studies out there, this article talks about two cases http://www.medpagetoday.com/Neurology/HeadTrauma/25433

      While cold lasers are quite expensive one can always get it cheaper cousin infrared LED for a tiny fraction of the price. This one is one of the more expensive LED units. It one by a Canadian company is very good imo http://www.healthrange.co.uk/sota-lightworks.php

      Delete
    3. By the way LED/LLLT light therapy is also believed to improve some aspects of mitochondrial function, which is one of the possible reasons for its benefits in traumatic brain injury.

      Delete
    4. I commented quite a bit about my long-term experience with LLLT and my use of it with my son (with autism) here:

      http://epiphanyasd.blogspot.com/2016/02/more-failed-autism-trials-and-28.html?showComment=1455412120540#c1078639673074665578

      Hope this helps Srh.

      Delete
    5. Tyler, I am very interested in therapies like these. Still using? Any new insights from your experience?

      Delete
    6. Have not done LLLT in quite a while because my son would sleep on his side and belly and not on his back. I use it personally though for various things (recovering from injuries faster, etc.). It helped but like some other therapies that were successful, sometimes they become impractical over time due to developmental changes like with LLLT or else with stuff like school and speech therapy which leaves very little time to get all this stuff done since I often have to cajole him into drinking the beverage in the morning that has most of what I give him. If something is not palatable and I can't mix it in a drink, then I can't do much about it right now since he won't do pills.

      Of course, if I built an infrared LED hat that fit on his head easily while he was sleeping, then it would be easy. There are red LED hats out there intended for men going bald, but those are shorter wavelengths (plain red as opposed to infrared) and so they don't penetrate the skull as well so while they might be good for the skin, they won't penetrate much into the brain.

      Delete
    7. Tyler, what is the recommended wavelength? Curiously, I decided to see how my son would react to this device I have that I use for my skin - it is 650nm. He loved it. I put it on his forehead, and then he moved it to his neck, at the base of his skull, and then to behind his right ear. I'm assuming my little device for skin isn't enough ? He loves it though... Maybe a coincidence but he has used it 3 nights in a row and has had the deepest, longest sleeps each night using it at bedtme.

      Delete
    8. That won't get any light onto the cortex. I think the optimum wavelength is like 860nm (I could not find the study in my disorganized bookmarks).

      These are what I use (not the brand as just about any brand will likely do):

      https://www.amazon.com/dp/B01LXYSAU5?psc=1

      Delete
  3. Hi Peter,
    We use mitospectra, have not really seen much change, but his pyruvic acid and some others came back abnormal, which our bio med doc said mito dysfunction.
    Going to start statins, he seems to be plateuing. He is starting to speak, but it is on & off, like a loose eletric wire some where.
    What is your opinion of Prozac (SSRI) small doses, have been recommended for his anxiety, some docs think anxiety causes stimming.
    Also, we have been an expensive version(apparently purified) of curcumin from a recommended pharmacy, not much effect.
    Thanks
    BK

    ReplyDelete
    Replies
    1. In the US prozac is quite often used in autism. Personally I do not think such drugs are a good choice. Stimming has different causes, but in many young children with autism the cause is oxidative stress. I would try NAC and other therapies before a drug like Prozac.

      Delete
  4. Does anyone have any thoughts about using for COPD Parkinson's & cardio myopathy as I have all three

    ReplyDelete
  5. Dear All,
    Miniperspective The Essential Medicinal Chemistry of Curcumin
    DOI: 10.1021/acs.jmedchem.6b00975
    This review suggest the currently available data are not reliable
    ---
    Curcumin is a constituent (up to ∼5%) of the traditional
    medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (panassay
    interference compounds) and an IMPS (invalid metabolic panaceas)
    candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No doubleblinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
    Yi

    ReplyDelete
  6. Overall, I tended to relieve in review article.
    Note most of lab articles are not reliable
    Prinz F, Schlange T, Asadullah K. Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov 2011;10:712.
    Hiltzik M. Science has lost its way, at a big cost to humanity. Los Angeles Times 2013. Available online: http://articles.latimes.com/2013/oct/27/business/la-fi-hiltzik-20131027. Accessed on 06 January December 2015.

    ReplyDelete

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