Glutathione and Parkinson's
Disease
[Scientific
Research Abstracts]
Glutathione,
oxidative stress and neurodegeneration
Schulz JB, Lindenau J, Seyfried J, Dichgans [J.Eur J Biochem
2000 Aug;267(16):4904-11] There is significant evidence that the pathogenesis
of several neurodegenerative diseases, including Parkinson's disease,
Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis,
may involve the generation of reactive oxygen species and mitochondrial
dysfunction. Here, we review the evidence for a disturbance of glutathione
homeostasis that may either lead to or result from oxidative stress
in neurodegenerative disorders. Glutathione is an important intracellular
antioxidant that protects against a variety of different antioxidant
species. An important role for glutathione was proposed for the pathogenesis
of Parkinson's disease, because a decrease in total glutathione concentrations
in the substantia nigra has been observed in preclinical stages, at
a time at which other biochemical changes are not yet detectable.
Because glutathione does not cross the blood-brain barrier other treatment
options to increase brain concentrations of glutathione including
glutathione analogs, mimetics or precursors are discussed.
Idiopathic
Parkinson's disease, progressive supranuclear palsy and glutathione
metabolism in the substantia nigra of patients
Perry
TL, Yong VW. [Neurosci Lett 1986 Jun 30;67(3):269-74] A significant
deficiency of GSH was found in the substantia nigra, but not in 5
other brain regions of PD patients, nor in PSP patients' brains. Glutathione
transferase activity was similar in the substantia nigra of PD, PSP
and control patients. Since total GSH is consumed only by conjugation
in detoxification processes, nigral GSH deficiency in PD patients
implies continued local presence of a possible causative neurotoxin
up to the time of death.
Alterations
in glutathione levels in Parkinson's disease and other neurodegenerative
disorders affecting basal ganglia
Sian
J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden
CD [Ann Neurol, 36(3):348-55 1994 Sep] Reduced glutathione (GSH)
and oxidized glutathione (GSSG) levels were measured in various brain
areas (substantia nigra, putamen, caudate nucleus, globus pallidus,
and cerebral cortex) from patients dying with Parkinson's disease,
progressive supranuclear palsy, multiple-system atrophy, and Huntington's
disease and from control subjects with no neuropathological changes
in substantia nigra. GSH levels were reduced in substantia nigra in
Parkinson's disease patients ..... the level of GSH in the substantia
nigra was significantly reduced only in Parkinson's disease. This
suggests that the change in GSH in Parkinson's disease is not solely
due to nigral cell death, or entirely explained by drug therapy, for
multiple-system atrophy patients were also treated with levodopa.
The altered GSH/GSSG ratio in the substantia nigra in Parkinson's
disease is consistent with the concept of oxidative stress as a major
component in the pathogenesis of nigral cell death in Parkinson's
disease.
Oxidative
stress as a cause of nigral cell death in Parkinson's disease and
incidental Lewy body disease
Jenner
P, Dexter DT, Sian J, Schapira AH, Marsden CD [Ann Neurol 1992;32
Suppl:S82-7]. We examine the evidence for free radical involvement
and oxidative stress in the pathological process underlying Parkinson's
disease, from postmortem brain tissue. The concept of free radical
involvement is supported by enhanced basal lipid peroxidation in substantia
nigra in patients with Parkinson's disease, demonstrated by increased
levels of malondialdehyde and lipid hydroperoxides. Levels of reduced
glutathione are decreased in nigra in Parkinson's disease; this decrease
does not occur in other brain areas or in other neurodegenerative
illnesses affecting this brain region (i.e., multiple system atrophy,
progressive supranuclear palsy). Altered glutathione metabolism may
prevent inactivation of hydrogen peroxide and enhance formation of
toxic hydroxyl radicals. In brain material from patients with incidental
Lewy body disease (presymptomatic Parkinson's disease), there is no
evidence for alterations in iron metabolism and no significant change
in mitochondrial complex I function. The levels of reduced glutathione
in substantia nigra, however, are reduced to the same extent as in
advanced Parkinson's disease. These data suggest that changes in glutathione
function are an early component of the pathological process of Parkinson's
disease.
Mitochondrial
impairment as an early event in the process of apoptosis induced by
glutathione depletion in neuronal cells: relevance to Parkinson's
disease
Merad-Boudia M, Nicole A, Santiard-Baron D, Saille C, Ceballos-Picot
I. [Biochem Pharmacol 1998 Sep 1;56(5):645-55] In Parkinson's
disease (PD), dopaminergic cell death in the substantia nigra was
associated with a profound glutathione (GSH) decrease and a mitochondrial
dysfunction. The fall in GSH concentration seemed to appear before
the mitochondrial impairment and the cellular death, suggesting that
a link may exist between these events.An approach to determine the
role of GSH in the mitochondrial function and in neurodegeneration
was to create a selective depletion of GSH in a neuronal cell line
in culture..... This treatment led to a nearly complete GSH depletion
after 24 hr and induced cellular death via an apoptotic pathway after
5 days of BSO treatment.... rapid GSH depletion was accompanied, early
in the process, by a strong and transient intracellular increase in
reactive oxygen species.... These results showed the crucial role
of GSH for maintaining the integrity of mitochondrial function in
neuronal cells. Oxidative stress and mitochondrial impairment, preceding
DNA fragmentation, could be early events in the apoptotic process
induced by GSH depletion. Our data are consistent with the hypothesis
that GSH depletion could contribute to neuronal apoptosis in Parkinson's
disease through oxidative stress and mitochondrial dysfunction.
Does
oxidative stress participate in nerve cell death in Parkinson's disease?
Hirsch
EC. [Eur Neurol 1993;33 Suppl 1:52-9] Parkinson's disease is characterized
by a massive neuronal loss in several cell groups of the midbrain.
However, the most consistent lesions are observed in dopaminergic
systems including nigral neurons. Although the cause of this neuronal
loss remains unknown, oxidative stress has been suspected to participate
in the mechanism of nerve cell death for several reasons. (1) Lipid
peroxidation, a consequence of oxygen free radical production, has
been found to be elevated in the substantia nigra in Parkinson's disease.
(2) Catecholaminergic neurons containing neuromelanin, an autooxidation
by-product of catecholamines, are more vulnerable in Parkinson's disease
than non-melanized catecholaminergic neurons. (3) Catecholaminergic
neurons surrounded by a low density of cells containing glutathione
peroxidase, a free radical scavenging enzyme, are more susceptible
to degeneration in Parkinson's disease than those well protected against
oxidative stress. (4) The content of iron, a compound which exacerbates
the production of free radicals in catecholaminergic neurons, is increased
in the substantia nigra in Parkinson's disease. It remains, however,
to be determined whether oxidative stress participates to the cause
of the disease or only represents a consequence of nerve cell death.
Altered
mitochondrial function, iron metabolism and glutathione levels in
Parkinson's disease
Jenner
P. [Acta Neurol Scand Suppl 1993;146:6-13] The mechanisms underlying
dopamine cell death in substantia nigra in Parkinson's disease remain
unknown. Current concepts of this process suggest the involvement
of free radical species and oxidative stress. ...there is evidence
for inhibition of complex I of the mitochondrial respiratory chain,
altered iron metabolism and decreased levels of reduced glutathione.
However,.... alterations in iron may be a response to, rather than
a cause of nigral cell death....However, there is a reduction in the
levels of reduced glutathione in substantia nigra in incidental Lewy
body disease of the same magnitude as occurs in advanced Parkinson's
disease. This would suggest that alterations in glutathione function
are an early marker of pathology in Parkinson's disease and may be
a clue to the primary cause of nigral cell death.
Depletion
of brain glutathione potentiates the effect of 6-hydroxydopamine in
a rat model of Parkinson's disease
Garcia
JC, Remires D, Leiva A, Gonzalez R.[ J Mol Neurosci 2000 Jun;14(3):147-53]
"The study examines the possible role of rat brain glutathione
depletion by diethyl maleate (DEM) in the potentiation of 6-hydroxydopamine
(6-OHDA) neurotoxicity, .....DEM injury makes the animals more susceptible
to brain-oxidative damage by 6-OHDA, which can indicate that in the
double-damaged animal group, DEM could induce potentiation of the
toxicity through striatal glutathione depletion.
Decreased
glutathione results in calcium-mediated cell death in PC12
Jurma
OP, Hom DG, Andersen JK. [Free Radic Biol Med 1997;23(7):1055-66]
Neuronal damage in certain cellular populations in the brain has been
linked to oxidative stress accompanied by an elevation in intracellular
calcium. Many questions remain about how such oxidative stress occurs
and how it affects calcium homeostasis. Glutathione (GSH) is a major
regulator of cellular redox status in the brain, and lowered GSH levels
have been associated with dopaminergic cell loss in Parkinson's disease
(PD). We found that transfection of antisense oligomers directed against
glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH
synthesis, into PC12 cells resulted in decreased GSH and increased
levels of ROS. Decreased GSH levels also correlated with an increase
in intracellular calcium levels. Data from this study suggest that
dopaminergic neurons are very sensitive to decreases in the internal
oxidant buffering capacity of the cell caused by reductions in GSH
levels, and that alterations in this parameter can result in disruption
of calcium homeostasis and cell death. These results may be of particular
significance for therapeutic treatment of PD, as those dopaminergic
neurons that are spared in this disorder appear to contain the calcium
binding protein, calbindin.
Glutathione
depletion switches nitric oxide neurotrophic effects to cell death
in midbrain cultures: implications for Parkinson's disease
Canals S, Casarejos MJ, de Bernardo S, Rodriguez-Martin E, Mena
MA. [J Neurochem. 2001 Dec;79(6):1183-95.] Nitric oxide (NO) exerts
neurotrophic and neurotoxic effects on dopamine (DA) function in primary
midbrain cultures. We investigate herein the role of glutathione (GSH)
homeostasis in the neurotrophic effects of NO. This study shows that
alterations in GSH levels change the neurotrophic effects of NO in
midbrain cultures into neurotoxic. Under these conditions, NO triggers
a programmed cell death with markers of both apoptosis and necrosis
characterized by an early step of free radicals production followed
by a late requirement for signalling on the sGC/cGMP/PKG pathway.
Glutathione
depletion in PC12 results in selective inhibition of mitochondrial
complex I activity. Implications for Parkinson's disease
Jha
N, Jurma O, Lalli G, Liu Y, Pettus EH, Greenamyre JT, Liu RM, Forman
HJ, Andersen JK. [J Biol Chem. 2000 Aug 25;275(34):26096-101]
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. 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.
[Case-control
study of markers of oxidative stress and metabolism of blood iron
in Parkinson's disease]
Larumbe Ilundain R, Ferrer Valls JV, Vines Rueda JJ, Guerrero D, Fraile
P. [Rev Esp Salud Publica 2001 Jan-Feb;75(1):43-53] Increasingly
growing evidence exists of the involvement of oxidative stress mechanisms
in Parkinson's disease. However, few studies have been made of levels
of antioxidants in the peripheral bloodstream and of the influence
of the intake of nutrients on the development of this disease. Significant
differences were found in the plasma levels of GSH between cases and
controls. The results of this study support the possible involvement
of oxidative stress in the pathogenesis of Parkinson's disease and
reveal, in turn, alterations in some peripheral blood parameters in
keeping with known findings in the sustantia nigra.
