David Cassarino dsc9w at avery.med.Virginia.EDU
Tue Dec 10 22:22:36 EST 1996

stephan at psych.ucla.edu  writes:
> 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.

There is loads of evidence that the vast majority of
Parkinson's disease (PD) is genetic.
Autosomal dominant forms of PD have been demonstrated, but the
inheritance of most cases looks "sporadic".  Recent evidence
has shown that these cases can often be interpreted as actually being
maternal (ie, mitochondrial).
Mitochondrial defects in the electron transport chain protein
complex I have long been known to characterize PD (Parker et
al), and these defects are systemic, not just in the
dopaminergic (DA) cells of the substantia
nigra (SN, the locus for degeneration in PD), consistent with
inheritance (but also with a toxin etiology).

Significantly, mitochondrial DNA (mtDNA)deletions and point mutations
have been demonstrated to be associated with PD (see papers by Ikebe,et al)
and it also is known that the complex I defect transfers
with mtDNA(Swerdlow et al), confirming its genetic etiology.

These mutations are thought to impair electron transport,
inhibiting ATP production, and generating free radicals, both
of which may be toxic to the cells.  The reason the SN
selectively dies in PD is most likely due to the high
concentrations of Fe and neuromelanin (not melatonin!) in the
SN, both of which generate free radicals, as does the oxidative
metabolism of DA itself. Free radical markers of damage to
proteins, lipids and DNA (nitrotyrosine, lipid peroxides, 
and deoxyguanosine, res.) are increased in PD tissues (again,
not just brain).  These effects ultimately lead to cell death,
probably through the apoptotic cascade. 

>The only two confirmed causes of Parkinson's are both
> 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.
No.  The mechanism of MPTP is well established--it's active
metabolite, MPP+ (produced in astrocytes NOT in "melatonin cells"
--which exist only in the pineal gland--diffuses into the
surrounding intercellular space and is uptaken by all cells,
but selectively concentrated in DA-neurons via the DA reuptake
transporter) inhibits complex I of the ETC--causing free
radical production, etc.  It also probably messes up calcium
buffering too, which may contribute to apoptosis (see the
Swerdlow paper).

BTW, the nigral cells are black because one of the products of
DA-metabolism is melanin (not melatonin, but the same stuff in
melanocytes, the pigmented cells in your skin which give rise
to moles and melanomas), which accumulates in
the nigra with aging and is thought to contribute to its
degeneration via enhanced free-radical gereration.
> (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.
> Cheers
> Stephan
> 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)
> > ------------
David S. Cassarino              "I wanted to live deep and suck out the 
MSTP, Neuroscience                 marrow of life...if it were sublime  
UVA School of Medicine               to know it by experience."
dsc9w at virginia.edu                                          -Thoreau

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