Re: MAPS: The role of heat and dopamine in MDMA neurotoxicity

["Little John" <saintjude2k@xxxxxxxxxxx>]

> Regarding whether the temperature rise is enough to be neurotoxic, once you
> hit about 40 oC (104 oF) or so, you induce so-called heat shock proteins
> which are supposed to help cells survive.  It is possible that some
> as-yet-unknown interaction between HSPs and an MDMA metabolite occurs which
> results in changes in axon morphology and 5-HT levels.  An earlier
> discussion on this list (with citations provided) pointed out that direct
> injection of MDMA into the brain does not produce the neuronal
> changes.  This argues strongly for a metabolite being the culprit.

         I don't feel it's necissary to go so far as a metabolite to find
the neurotoxic species.     MAO-B inhibitors have proven to be
neuroprotective against MDMA (which may be due to inhibition of MAO-B or of
other enzymes that have similar substrate affinities.)     Why not local
deamination of the MDMA itself as the metabolic source of the oxidative
species (superoxide?  hydroxyl radical?)      When the locallized perfusion
experiments were done, there was an assumption of 'simple' toxicity, not
taking hyperthermic response into consideration as a major aggrevating
factor.    While the local injection failed to produce toxicity, it also, I
believe, failed to produce a significant hyperthermic response, without
which little if any neurotoxicity would be expected.    The 'toxic
metabolites' proposed (various results of methylenedioxy ring
cleavage/conjugation/N-demethylation of MDMA) could simply be toxic by the
same pathway as MDMA itself, via the process of deamination of their
isopropylamine tail.   None of which is to say MDMA metabolites can't be
significant or even sole sources of neurotoxicity, only that a simpler
explanation may suffice.
       We're getting so maddeningly, wonderfully close, though.    The
answers keep coming...I really do believe we're close to being able to give
a Carved In Stone By God level of confidence explanation for MDMA's
fascinating neurotoxicity.   (Which is also to say I don't think we're there
yet.)


____________________
Reality is an aproximation of the Math.

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