Glutatheione conjugated alpha-MeDA metabolites of MDA and MDMA.

[2CEECS]

Hey all,

I'm having a hard time deciphering the some of the abstracts available on how N-methyl-alpha-MeDA conjugated with glutathione may explain serotonergic neurotoxicity of systemically-administered MDMA and MDA. In particular, what I've read seems to imply to me that GSH is actually part of the problem, and so supplementing Glutathione could worsen the problem. Yet others recommend it as a preload, and in normal functioning is a helpful antioxidant. It seems in some cases it may form more dangerous compounds, instead of neutralizing oxidizers in unconjugated form.

If my understanding is correct, it may be the case that Glutathione is helpful because it competes with the conjugated metabolites for actual uptake into the brain. Is this right?

Any other comments or pointers to consolidated information about this are appreciated. There seems to be only one post on BL that references N-methyl-alpha-MeDA, that I could find.

Finally, in particular, does anyone know how neuroprotection via MAO-B inhibition ties into the toxic metabolite theory? Are these alpha-MeDA compounds metabolized by MAO-B?

Awesome collection of references:
http://www.neurotransmitter.net/mdmametabolites.html

Some interesting ones mentioning -MeDA varieties:
http://www.ncbi.nlm.nih.gov/pubmed/11453733
http://www.ncbi.nlm.nih.gov/pubmed/15169827
http://www.ncbi.nlm.nih.gov/pubmed/15228153
http://www.ncbi.nlm.nih.gov/pubmed/15634943
http://www.ncbi.nlm.nih.gov/pubmed/17467183

One such recommendation of use of N-Acetylcysteine (GSH precursor) as a preload:
http://www.bluelight.ru/vb/showthread.php?t=387505

Thanks!!

 

[hamhurricane]

RZ is quite knowledgeable regarding this topic and perhaps he will chime in - i don't know about direct supplementation with glutathione but as you said N-acetyl-cysteine is a glutathione precursor and the in vivo metabolism of alpha-methyl-dopaminoquinone depletes glutathione stores, NAC is considered neuroprotective with MDx but i see what your saying as GSH seems both protective and necessary for the production of toxic conjugates.

 

[fly-]

According specificaly with this article:

Abstract
The selective serotonergic neurotoxicity of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) depends on their systemic metabolism. We have recently shown that inhibition of brain endothelial cell gamma-glutamyl transpeptidase (gamma-GT) potentiates the neurotoxicity of both MDMA and MDA, indicating that metabolites that are substrates for this enzyme contribute to the neurotoxicity. Consistent with this view, glutathione (GSH) and N-acetylcysteine conjugates of alpha-methyl dopamine (alpha-MeDA) are selective neurotoxicants. However, neurotoxic metabolites of MDMA or MDA have yet to be identified in brain. Using in vivo microdialysis coupled to liquid chromatography-tandem mass spectroscopy and a high-performance liquid chromatography-coulometric electrode array system, we now show that GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA are present in the striatum of rats administered MDMA by subcutaneous injection. Moreover, inhibition of gamma-GT with acivicin increases the concentration of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA in brain dialysate, and there is a direct correlation between the concentrations of metabolites in dialysate and the extent of neurotoxicity, measured by decreases in serotonin (5-HT) and 5-hydroxyindole acetic (5-HIAA) levels. Importantly, the effects of acivicin are independent of MDMA-induced hyperthermia, since acivicin-mediated potentiation of MDMA neurotoxicity occurs in the context of acivicin-mediated decreases in body temperature. Finally, we have synthesized 5-(N-acetylcystein-S-yl)-N-methyl-alpha-MeDA and established that it is a relatively potent serotonergic neurotoxicant. Together, the data support the contention that MDMA-mediated serotonergic neurotoxicity is mediated by the systemic formation of GSH and N-acetylcysteine conjugates of N-methyl-alpha-MeDA (and alpha-MeDA). The mechanisms by which such metabolites access the brain and produce selective serotonergic neurotoxicity remain to be determined.

http://www.ncbi.nlm.nih.gov/pubmed/15634943?dopt=Abstract

It seems NAC does increase neurotoxicity, but protects at the same time? Its safe to assume that using NAC as neuroprotective supplement is a bad move with MDMA?

 

[reformer]

GSH Conjugated Quinones from Flavonoids also Toxic

I am not sure if the previously demonstrated phenomena of glutathione (GSH) conjugation altering biological effects of flavonoids toward a toxic profile is directly relevant to the OP's question, but I think there are some distinct parallels.

I'm trying to dig up the reference, but suffice it to say that the metabolism of ortho and para phenolic compounds of the flavonoid class can oxidize to quinones and subsequently be conjugated to GSH. At least one published study has demonstrated that the GSH conjugated quinone metabolites of polyphenolic flavonoids are more toxic than the quinone intermediates themselves.

I believe the reasoning the authors invoked had to do with GSH dumping electron density onto the aromatic ring and altering the reduction/oxidation potential of the quinone. The end result was an increased capacity for redox cycling with superoxide/hydrogen peroxide production and consumption of cellular reducing equivalents.

If I can dig up the original reference I'll come back and post it...

r

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EDIT:

As I ruminate on this further, I can't quite recall if the study actually demonstrated toxicity, or if the study I was alluding to above only showed that the redox cycling capacity of GS-Flavonoid conjugates were altered and then the authors went on to conclude that there was *potential* for increased toxicity.

r