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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.

Read our special report on:
Glutathione in the etiology and treatment of Parkinson's Disease



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