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Dear List friends,

This  is a subject that surfaces every now and then, and is met by searchers
with  hope, and by members of the medical community with  a blanket
disclaimer ...... " It's not  proven  .....  its not  FDA approved"  Let's
set the BS aside and take an honest  look at this poor  biochemical whipping
child.

First of all, Glutathione does not do a good job of crossing the blood
barrier from the gastrointestinal track, so "direct" supplementation does
not work. It is, however, possible to stimulate   the regeneration or
production of it by the liver, if you are not into IV injections .....

Oxidative stress appears to play an important role in degeneration of
dopaminergic neurons of the substantia nigra (SN) associated with
Parkinson's disease (PD). The SN of early PD patients have dramatically
decreased levels of the thiol tripeptide glutathione (GSH). GSH plays
multiple roles in the nervous system both as an antioxidant and a redox
modulator. We have generated dopaminergic PC12 cell lines in which levels of
GSH can be inducibly down-regulated via doxycycline induction of antisense
messages against both the heavy and light subunits of
gamma-glutamyl-cysteine synthetase, the rate-limiting enzyme in glutathione
synthesis. Down-regulation of glutamyl-cysteine synthetase results in
reduction in mitochondrial GSH levels, increased oxidative stress, and
decreased mitochondrial function. Interestingly, decreases in mitochondrial
activities in GSH-depleted PC12 cells appears to be because of a selective
inhibition of complex I activity as a result of thiol oxidation. These
results suggest that the early observed GSH losses in the SN may be directly
responsible for the noted decreases in complex I activity and the subsequent
mitochondrial dysfunction, which ultimately leads to dopaminergic cell death
associated with PD.

The brain carries a high endogenous oxidative burden. First, by having
myelin sheaths the neurons are particularly enriched in polyunsaturated
lipids. A low  or no fat diet is not the answer! Polyunsaturated  fats are a
very necessary part of the diet to insure protection. Due to their high
density of carbon-carbon double bonds, these lipids are prime targets for
oxidative attack. Second, the brain consumes a disproportionately high share
of the body's oxygen intake, creating a correspondingly high flux of
endogenous oxyradical formation. Third, the activities of the antioxidant
enzymes catalase and peroxidase are abnormally low in the brain. The
superoxide dismutase enzymes are active, acquiring superoxide oxyradical as
it leaks out of the mitochondrial complexes and converting it to hydrogen
peroxide (H2O2). But in the virtual absence of catalase and peroxidase,
which normally would detoxify these peroxide products, the burden for
detoxifying H2O2 is shunted onto the glutathione peroxidase enzyme. This
enzyme uses glutathione (GSH) as its essential cofactor, and when it is
adaptively induced the brain's GSH reserves are likely rendered more prone
to depletion from oxidative attack. Multiple studies confirm that the
brain's substantia nigra region is abnormally depleted of GSH in PD patients


Environmental agents implicated in the etiology of PD include pesticides,
oxidant transition and heavy metals (iron, copper, zinc, manganese, mercury,
lead, aluminum), and certain food-borne toxic agents, all of which can
readily be categorized as oxidative stressor agents. What all these diverse
agents have in common is their capacity to challenge the fragile antioxidant
status of the SN and deplete its GSH content. The evidence strongly suggests
glutathione depletion is the pivotal event in Parkinson's etiology.
Glutathione is a potent molecular anti-oxidant, a conjugation cofactor for
the liver P450 system, and an essential cofactor for the glutathione
peroxidase family of antioxidant enzymes. GSH also plays higher-level roles
in metabolism: anti-inflammatory, anti-toxin, and metabolic regulator. Its
levels are homeostatically maintained inside the living cell, where the
self-adjusting mechanisms for maintaining GSH are numerous. GSH levels may
well be a life gauge: that is, for as long as its levels are maintained the
living cell is healthy and functional, and once it is severely depleted the
cell is destined to die.

Evidence is growing that GSH depletion contributes to neurodegenerative
diseases. In numerous animal models of GSH depletion, the blockage at birth
of the animal's capacity for GSH synthesis distorts brain development. In
young or adult animals, GSH blockage results in neuronal pathology. Specific
clinical evidence in Parkinson's disease also points to GSH depletion as the
common thread.

The features of this model most relevant to PD are GSH degradation in the
SN, and its overlap with the presence of oxidative stressors. A source of
oxidative stress need not be just a toxin - it can be insufficiency of
dietary antioxidants or mineral enzyme cofactors, impairment of antioxidant
enzyme synthesis, or the overall decline of antioxidant defense capacity
with advancing age. Furthermore, the negative synergy between GSH depletion
and oxidative stress certainly need not result only in PD.

This GSH-depletion model predicts the clustering of neurodegenerative
disease symptoms sometimes clinically observed in the same individual,
including Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and PD.
The Bains and Shaw model of pathologic GSH depletion also predicts that
populations most at risk for developing diseases such as PD, Alzheimer's,
and ALS are those at the low end of the overall range for GSH.45 They
propose that "low-glutathione" individuals exist in the population, "primed"
for initiation of PD or other neurodegenerative progression. Glutathione
depletion could arise in various ways, including genetic propensity, poor
diet, pharmaceutical treatment (as with acetaminophen use), or as a function
of age. An Italian clinical team reported that intravenous administration of
GSH to newly-diagnosed PD patients resulted in marked improvement in motor
ability in nine patients.These findings were substantiated by Dr.Perlmutter
(Sorry, according to Dr. Lieberman, not Proven )

Milk thistle has been around  and used for some 2000 years to aid with liver
detoxification.  Milk Thistle's main active bioconstituent is Silymarin.
Silymarin selectively acts as an anti-oxidant and protects the b.d. from
free radical damage specifically in the intestines and stomach. It increases
the liver's content of GSH (glutathione) which is a substance in detoxifying
many potentially damaging hormones, chemicals, and drugs (including
acetaminophen)  It has demonstrated a membrane stabilizing action, which
inhibits or prevents lipid peroxidation. It seems to alter the structures of
outer wall membranes of hepatocytes, preventing penetration of liver poisons
and stimulates the action of nuclear polymerase A. It may increase ribosomal
protein synthesis and stimulate the formation of new hepatocytes.

For something that the  medical community doesn't want to discuss, we do
know an awful lot about it.  As we have seen in the past, there are many
things which are not FDA  approved. Many things that have not been  proven
to work for the whole of PWP, BUT some of these do give relief to a few
because of the inconsistant nature of PD. For some reason  there is an
attempt to discredit these things that to work for  some folks. What a shame
and at what  price..... Like lambs to the slaughter, are we all condemmed to
only follow the "proven " path?  Let us all try to keep our minds and hearts
open, for that is the only way that we can increase understanding and open
our eyes to what may in the future be a relief for our burden if not a cure
to our unwanted guest.

Thank you for your  consideration, and although this has just scratched the
surface, I hope that it  has increased  the understanding  concerning
glutathione a little bit.  Rob

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