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Melatonin and AR in SBMA
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Registered: 08-05-2012
Posts: 7
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hey,

here is may be something interessting.
The whole work is sadly in German.

PM me for the whole Work.

Abstract:
Spinal and bulbar muscular atrophy (SBMA) is one of nine neurodegenerative diseases
known to date which can be traced back to amplification of polyglutamine tracts (polyQ)
in different proteins. In SBMA, the affected protein is the ligand-dependent androgen
receptor (AR) whose polyQ tract comprises 9-38 glutamine residues in healthy
individuals. In SBMA patients, the polyQ stretch is expanded to 40 and up to more than
60 polyQ though. This leads to misfolding and aggregation of the mutant androgen
receptor protein causing the degeneration of specific motor neurons which elicits
locomotor impairments in SBMA patients. To date, no therapy for SBMA is available.
However, recently a Drosophila model which expressed the mutant AR panneuronally
has shown that the hormone melatonin can restore the locomotor ability of these
transgenic flies.
The aim of this work was to create an SBMA-specific Drosophila model with selective
expression in motor neurons of different AR constructs (the wild type AR, ARQ22, a
deletion mutant carrying one glutamine, ARQ1, the polyQ-amplified AR, ARQ65 and the
wild type AR with two amino acid exchanges at serine residues 424 and 514 by
exchanging them to alanine which was recently shown to confer toxicity to the wild type
AR, ARQ22dm). The impact of these AR constructs and the effect of melatonin were
analyzed in the AR-transgenic flies in locomotor and survival assays. Additionally,
cellular systems were used to explore the mechanisms by which melatonin interferes
with the AR action.
The results of this work showed that the motor neuron-specific expression of the wild
type androgen receptor and ARQ1 did not lead to any defects in the Drosophila model
whereas ARQ65 and ARQ22dm expression evoked a severe locomotor defect in the
presence of the AR ligand dihydrotestosterone (DHT). This phenotype was rescued by
the application of melatonin. In cultured insect cells, the expression of ARQ65 and
ARQ22dm significantly decreased cell viability which was also inhibited by melatonin.
Further characterization of the expression of the AR constructs and the effects of
melatonin was performed in mammalian cells. The expression of the polyQ-expanded
AR resulted in the appearance of large macromolecular aggregates in the cytoplasm of
the cells. These aggregates reached sizes of 2.5 μm in diameter after 6 hours of DHT
treatment. The number of aggregate-positive cells was significantly reduced by
incubating the cells with melatonin. Furthermore, mutagenesis of the important N- and
C-terminal interaction surface of the androgen receptor which stabilizes the AR and
allows transcriptional regulation prevented the formation of the macromolecular
aggregates. This suggests that N- and C-terminal interactions contribute to the
aggregation and toxicity of the mutant receptors. However, subsequent studies revealed
that the rescue effects of melatonin were not mediated via the N/C interaction of the AR
as melatonin did not block this interaction.
In summary, the results of this work show that melatonin can interfere with the action
of the pathologic AR insofar as it prevented experimental models of SBMA from toxic
AR-induced defects. The studies presented here exclude N- and C-terminal interaction of
the AR as basis of the rescue effect of melatonin.
Picture of Lolo
Location: Arizona
Registered: 10-06-2010
Posts: 108
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Oh nice! I take melatonin everyday and now will try some on my husband. Any idea how much? I take 2 - 5mg about 2 hrs before bed.
Registered: 08-02-2009
Posts: 195
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The original paper in German is "Die Wirkung von Melatonin auf den Androgenrezeptor
in experimentellen Modellen von spinaler und bulbärer Muskelatrophie", available at this link. There is also an English abstract at that link.

Unfortunatly, it is an "in vitro" study, meaning it was done in a glass dish instead of a live subject. Even so, it is good to know there is a possible new avenue of treatment for SBMA. Even better, melatonin is a commonly-available, over-the-counter substance, so if it works, it'll be affordable.

This message has been edited. Last edited by: Dan B,
Registered: 08-02-2009
Posts: 195
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There is another scientific paper that covers melatonin and SBMA, this one thankfully in English, or at least what passes for English among scientists.

Citation is: Biochim Biophys Acta. 2012 Jun;1822(6):1070-8. Epub 2012 Feb 15.
Toxic and non-toxic aggregates from the SBMA and normal forms of androgen receptor have distinct oligomeric structures.
It is abstracted at this link.

Again it is an "in vitro" study, so no information about results in live subjects or possible dosages.
Picture of Lolo
Location: Arizona
Registered: 10-06-2010
Posts: 108
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Why not start taking it daily like I do? I don't think it can hurt you. Sure would be amazing if it really helped!
Registered: 08-02-2009
Posts: 195
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Hi Lolo,

Thanks very much for your comment. It is true that melatonin is sold in drugstores, and it is often recommended to promote sleep for people who have insomnia or jet lag.

However, it is extremely important to keep in mind we are not doctors nor pharmacists. Gotta be careful about saying things like, "I don't think it can hurt you," because sometimes medications interact in ways that aren't predictable. Sometimes it can hurt you.

Anyone who contemplates taking melatonin should read the label carefully and probably discuss with your doctor or pharmacist beforehand. Also remember to update your doctor on which over-the-counter items you are taking (if any) before starting any new prescriptions.

Also keep in mind this is all very speculative. There is no proof that melatonin has anything to do with SBMA in humans. It hasn't even been tested in mice or other animals yet.

This message has been edited. Last edited by: Dan B,
Registered: 08-05-2012
Posts: 7
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quote:
Again it is an "in vitro" study, so no information about results in live subjects or possible dosages.


Yes! This does not show how it works in Human.
Anyway, it is a Hormon!!!
Registered: 08-02-2009
Posts: 195
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Found two additional papers that address the question of melatonin. Titles are:
  • Specific N-terminal mutation in the human androgen receptor induce cytotoxicity, Neurobiology of Aging 30 (2009) 1851-1864
  • Nuclear exclusion of the androgen receptor by melatonin, Journal of Steroid Biochemistry 81 (2002) 77-84.
The full text can be found by searching on Google.

Here's a quotation from the first paper:
quote:
"We thus established that both sodium butyrate and melatonin are effective inhibitors of polyQ toxicity in our model system....The differential effects of sodium butyrate and melatonin in rescuing specific subsets of the toxic action of polyQ stretches in our study therefore strongly support the idea of combinatorial drug regimens for the future treatment of polyQ disorders."
Unfortunately, their "model system" was in fruit flies, so it's way too early to suggest that humans should start taking melatonin for the protective effect.

There's one additional point that's interesting. The standard notion is that testosterone is toxic to men with SBMA, but there's no explanation why testosterone shows up around age 13, but symptoms of SBMA don't show up until 30 years later or more. In fact, levels of testosterone usually drop with age, so it makes no sense that SBMA should get worse as you get older and your testosterone level is lower.

However, melatonin levels are also believed to lower with age. So if melatonin is somehow protecting against SBMA, it makes sense that SBMA symptoms would get worse as you get older and your melatonin level drops.
Registered: 05-07-2007
Posts: 46
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Hi Dan,

The melatonin info looks interesting. The major problem I can see (assuming that the results are 'good') is that the levels in the mice and cells that produce the effect is much higher than normal levels of melatonin in humans.

For example, one of the cell studies has a melatonin concentration is about 75 times greater than that found in humans; one of the mice studies injected 30 mg/kg per day. If I did the math correctly, for a 60 kg human, one would have to inject 1800 mg per day to have the same dose. Since melatonin comes in 5 mg pills, one would have to ingest (assuming ingestion is as efficient as injection) 360 pills per day (I saw on bottle with 'only' 265 pills for sale!). The typical (high) dose for humans is 1 pill per day. I would be surprised if the safety of the side effects of such high levels has been sufficiently tested not to mention there is no evidence to show it is effective in humans.

The other comment about the progression of the KD is one of the big mysteries of CAG diseases. One interesting suggestion is based on the fact that the size of the CAG repeat in cells changes as one gets older. This is not uniform in all cells (and may not occur in most cells), but can be observed (at least in mice). This is believed to be due to the activity of a DNA repair enzyme. Fewer CAG changes are noted if the mice are missing this enzyme. For reasons that are not clear (at least to me), these changes generally trend to increasing the CAG repeats. So it could be that the actual number of repeats that is toxic is higher than what we were born with and we do not reach that level until we get older. In addition, this hypothesis would explain why the CAG repeat diseases have an earlier onset with a higher original CAG number.
Location: Dallas, TX
Registered: 12-03-2012
Posts: 14
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I have had the best sleep in my life after learning about melatonin. I started by taking the pill(OTC) but realized they are not needed. We get it for free by reducing the lights. The more light we block the more melatonin we make.
I use a sleep mask to black out all light and if a sleep mask is not handy I just lay a t-shirt over my eyes.
It has been life changing. I sleep so much deeper and fall asleep quicker.
Registered: 08-02-2009
Posts: 195
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Melatonin has now been shown to have a protective effect on neurons in mouse models of both ALS (Lou Gehrig's Disease) and Huntington's Disease.
http://alsn.mda.org/news/melat...ate+-+Fam+-++5+10+13
http://www.hdsa.org/research/n...in-mouse-models.html

In this episode of the series "The Brain" on Charlie Rose, near the very end of the recording he can be heard interviewing a man who took melatonin for Huntington's Disease with good results. So it's not just for mice.
http://www.charlierose.com/view/interview/12408

This message has been edited. Last edited by: Dan B,
Picture of Lolo
Location: Arizona
Registered: 10-06-2010
Posts: 108
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Dan, you were right in correcting me. I agree, one should discuss all meds and OTC with their Dr.

I take Valerian root and melatonin as well as use a sleep mask as I have such difficulty getting to sleep. All my doctors are aware of this as well as other meds and OTC.

If using a sleep mask, look for one with a wide elastic strap as the tiny ones wear out and stretch. Also, I now only buy the masks that have molded eye covers so my eyes are not blurry in the morning. The flat masks will squeeze your eyes and can distort vision for some time after waking. I buy my sleep masks from Ebay. If anyone wants to know which one, just contact me. They do come from China and are not expensive.
Registered: 01-27-2014
Posts: 22
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Your physique has its own particular inward clock that controls your characteristic cycle of dozing and waking hours. Partially, your physique clock controls what amount of melatonin your physique makes. Regularly, melatonin levels start to ascent in the mid- to late nighttime, remain high for a large portion of the night, and after that drop in the unanticipated morning hours.
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