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Stephan Anagnostaras stephan at psych.ucla.edu
Sat Nov 23 07:21:04 EST 1996

Yes, the good humor of this all is that MPTP, the toxin accidentally
produced in SF by drug "designers" making synthetic heroin and which
produces a severe Parkinson's syndrome, was actually developed by
Gulf chemical as a pesticide named Cyperquat.  It was never marketed,however,
because if lethal effects in animals.  The reason Paraquat and Diquat
have generated interest is because they are chemically very similar --
but, as far as I know, this isn't very interesting because they dont
produce Parkison's in animal models the way MPTP (and MPP+, which is
the active metabolite) does. 

THe "cause" of most Parkinson's is not known <called "idiopathic" for,
my doctor is an idiot who likes big words :) JK! >
There are several theories, most
of which are ENVIRONMENTAL, not genetic.  Most genetic theories of Parkinson's
emphasize increased susceptibility to the environmental agents for one
reason or another, although some people believe that there is purely
genetic Parkinson's.

The only two confirmed causes of Parkinson's are both environmental:

1. one type of encephalitis virus

2. MPTP. The exact mechanism of MPTP toxicity is not known, except as
follows. MPTP is converted to MPP+ in melatonin cells (the black ones)
in the nigra, and then secreted where it is taken up by DA cells
and kills them. THe likely mechanism is that mitochondria are poisoned,
by messing up their ability to store calcium.  Because MPTP relies
on melatonin cells, it doesn't work in rats (which do not have black
nigras) but it MPP+ works fine.

(3) I think there is a recent report of confirmed genetic Parkinson's,
I wouldn't necessarily take this too seriously, since the question is
what proportion of the disease is caused by what, not whether or not
genetic causes MAY exist. This is similar to cancer, where although
genetic causes do exist for some cancers, for the most part genetic
contributions to cancer etiology are relatively small.  This may or
may not be the case with Parkinson's, but based on animal studies 
where animal's are exposed to potent toxins of DA cells there isn't
really much variability in the susceptibility of the animals to the toxin
<but the question remains: do lots of these toxins really exist in
the environment?>

There are other toxins which have been developed which also kill dopamine
cells, the most notable is 6-hydroxydopamine which has been used in
animal models for years.  Exposure to these chemicals can produce a
severe Parkinsonism.

Now the story is, what proportion is caused by what. One idea is
genetic, the other essentially is an unknown list of environmental agents.
A number of epidemiological studies show that Parkinson's occurs in
pockets; this has been interpreted as environmental, but is actually
consistent with either explanation. More than likely, Parkinson's
has several major causes, at least one of which is probably
some kind of environmental toxin. This does not preclude the possibility
that a strict form of genetic Parkinson's may also exist, or the more
likely case that some genetic trait may make some people's SN cells
more susceptible to damage than others.


In article <3293C540.4FA0 at Ifn-magdeburg.de>, Christopher Hatton
<Hatton at Ifn-magdeburg.de> wrote:

> > In article <Pine.LNX.3.95.961117201558.24859A-100000 at shell1.erols.com>
DR JERRY CHANDLER <jlrchand at erols.com> writes:
> > >From: DR JERRY CHANDLER <jlrchand at erols.com>
> > >Subject: Re: Parkinsons-Pesticides
> > >Date: Sun, 17 Nov 1996 20:21:48 -0500
> > 
> > 
> > >If my memory serves me correctly, two chemical agents - paraquat and
> > >diquat - may be of interest to you.  Perhaps this effect was discovered
> > >among illicit drug users who inhaled significant quantities of these
> > >agents.  Discovery of these agents started a flood of research on the
> > >mechanism of action and the disease - genesis processes.
> > >I would assume that any recent toxicology text or Toxline would provide
> > >further information.  
> > >If further help is urgently needed, you can call me at the number given
> > >below.
> > 
> > I have a vague memory of a biochemistry seminar where it was pointed
out that 
> > a contaminant in designer drugs caused parkinson-like symptoms. It
worked by 
> > inactivating mitochondria, those in one particular part of the brain were 
> > particularly susceptible. It's quite possible that a pesticide could
have the 
> > same effect, though someone would have to have looked for it.
> > 
> I also remember from a not so distant Toxicology lecture, something
> similiar, so I delved into my notes and Leonard's Fundamentals of
> Psycopharmacology(1992) and Timbrells "Principals of Biochemical
> toxicology"(1991)
> n-methyl-4-phenyl-pyridinium, is the contaminate and the metabolite MPP+
> is the neurotoxin and destroys dopamine preoducing cells.  Leonard
> speculates that herbicides may produce the same symptoms.  I myself
> would go along with that and now I would sugges that metabolites in
> small concetration would cross blood brain barrier after
> biotransformation by Cyto. P450's on the endothelia cells. (haven't any
> proof mind) 
> except that Paraquat is a bipyridylium compound, toxic in the lung
> principally probably therfore metabolised similarly.
>  Also that it uses the polyamine uptake system for putrescine and
> spermine,   It is most toxic when bound to the redox NADP+ /NADPH cycle
> producing lots of superoxide and depleting glutathione levels.
> If anybody want to other me a job/studentship in this area, I be most
> interested, because many "pesticides" induce Cyto. P450 expression, not
> just in the liver, but lung and brain also.  I've loads of ideas, but
> they fall on deaf ears here.
> Christopher Hatton
> Institute for Neurobiology
> Magdeburg
> Germany.
> -------------
> Is life just a game where we make up the rules while we are searching 
> for something to say, or are we just simply spirals of self replicating
> DNA.
> (Monty Python- from the meaning of life).
> http://www.ifn-magdeburg.de
> Please note that the above views are my own and not (just) those of the
> IfN.(hehe)
> ------------

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