Depree, Jonathan A depreej at lincoln.ac.nz
Mon Nov 25 15:04:30 EST 1996

In article <stephan-ya023280002311960421040001 at news.ucla.edu> stephan at psych.ucla.edu (Stephan Anagnostaras) writes:
>From: stephan at psych.ucla.edu (Stephan Anagnostaras)
>Subject: Re: Parkinsons-Pesticides
>Date: Sat, 23 Nov 1996 04:21:04 -0800

>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. 

Now that's interesting! In view of your later comments about rat brains, what 
are the 'animals it doesn't work in?

>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?>

Woah there! My understanding of cancer is that it is caused by one or more 
regulatory genes being knocked out, either by an inherent fault or by damage 
by mutagens -or a combination of both.
Whether or not the idea of a heritable Parkinson's disease should be taken 
seriously depends on the evidence for it, not a preconcieved model. Either way 
it doesn't seem to me that Parkinson's and cancer have that much in common.

>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.

Makes sense.

>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)
>> ------------

Jonathan Depree,
Lincoln University, P.O. Box 84, Canterbury, New Zealand.

Socrates was a famous Greek Teacher who went around giving
people advice. They killed him.   (school history howler)

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