Reduced intravenous glutathione in the treatment of early parkinson's disease

doi:10.1016/S0278-5846(96)00103-0

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 20, Issue 7, October 1996, Pages 1159-1170

https://doi.org/10.1016/S0278-5846(96)00103-0 Get rights and content

Abstract

1.
1. Several studies have demonstrated a deficiency in reduced glutathione (GSH) in the nigra of patients with Parkinson's Disease (PD). In particular, the magnitude of reduction in GSH seems to parallel the severity of the disease. This finding may indicate a means by which the nigra cells could be therapeutically supported.
2.
2. The authors studied the effects of GSH in nine patients with early, untreated PD. GSH was administered intravenous, 600 mg twice daily, for 30 days, in an open label fashion. Then, the drug was discontinued and a follow-up examination carried-out at 1-month interval for 2–4 months. Thereafter, the patients were treated with carbidopa-levodopa.
3.
3. The clinical disability was assessed by using two different rating scale and the Webster Step-Second Test at baseline and at 1-month interval for 4–6 months. All patients improved significantly after GSH therapy, with a 42% decline in disability. Once GSH was stopped the therapeutic effect lasted for 2–4 months.
4.
4. Our data indicate that in untreated PD patients GSH has symptomatic efficacy and possibly retards the progression of the disease.

References (21)

T.L Perry et al.
Parkinson's disease: a disorder due to a nigral glutathione deficiency
Neurosci Lett
(1982)
B.V. Zlokovic et al.
Evidence for transcapillary transport of reduced glutathione in vascular perfused guinea-pig brain
Biochem Biophys Res Commun
(1994)
E.M. Cornford et al.
Bloodbrain barrier restriction of peptides and the low uptake of enkephalins
Endocrinology
(1978)
H. Ehringer et al.
Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gemirn des Menschen und ihr Verhalten bei Erkrankungen des Extrapyramidalen Systems
Klin Wochenschr.
(1960)
S.I. Harik et al.
The protective influence of the locus coeruleus on the blood-brain barrier
Ann Neurol
(1984)
P. Jenner
Altered mitochondrial function, iron metabolism and glutathione levels in Parkinson's disease
Acta Neurol Scand
(1993)
P. Jenner et al.
New insights into the cause of Parkinson's disease
Neurology
(1992)
T.H. Mcneil et al.
Glutathione depletion mimics MPTP neurotoxicity and age-correlated changes in dopamine neurons in substantia nigra of the C 57BL/6NNia mouse
Soc for Neuroscience Abstracts 12
(1986)
A. Meister et al.
Glutathione and related gamma-glutamyl compounds: biosynthesis and utilization
Ann Rev Biochem
(1976)

There are more references available in the full text version of this article.

Cited by (136)

Metabolomics comparison of metabolites and functional pathways in the SH-SY5Y cell model of Parkinson's disease under PEMF exposure
2024, Heliyon
PEMF is an emerging technique in the treatment of Parkinson's disease (PD) due to its potential improvement of movement speed. The aim of this study was to investigate the metabolic profiles of pulsed electromagnetic fields (PEMFs) in an SH-SY5Y cell model of PD.
The SH-SY5Y cell model of PD was induced by 1-methyl-4-phenylpyridinium (MPP⁺). Liquid chromatography mass spectrometry (LC‒MS)-based untargeted metabolomics was performed to examine changes in the PD cell model with or without PEMF exposure. We conducted KEGG pathway enrichment analysis to explore the potentially related pathways of the differentially expressed metabolites.
A total of 275 metabolites were annotated, and 27 significantly different metabolites were found between the PEMF treatment and control groups (VIP >1, P < 0.05), mainly including 4 amino acids and peptides, 4 fatty acid esters, 2 glycerophosphoethanolamines, 2 ceramides and 2 monoradylglycerols; among them, 12 metabolites were upregulated, and 15 were downregulated. The increased expression levels of glutamine, adenosine monophosphate and taurine were highly associated with PEMF stimulation in the PD model. The enrichment results of differentially abundant metabolite functional pathways showed that biological processes such as the mTOR signaling pathway, PI3K-Akt signaling pathway, and cAMP signaling pathway were significantly affected.
PEMFs affected glutamine, adenosine monophosphate and taurine as well as their functional pathways in an in vitro model of PD. Further functional studies regarding the biological effect of these changes are required to evaluate the clinical efficacy and safety of PEMF treatment in PD.
An Off-Off fluorescence sensor based on ZnS quantum dots for detection of glutathione
2023, Journal of Photochemistry and Photobiology A: Chemistry
Citation Excerpt :
As a common tripeptide, Glutathione (GSH) exists in nearly every cell of the body [1]. It is an important intracellular regulatory substance [2–5] with antioxidant, free radical scavenging, immunity enhancement and other functions [6]. Therefore, it is of great significance to develop a simple, rapid and highly selective method for the determination of GSH.
Quantum dots (QDs) are excellent fluorescent indicators for chemical and biological analysis. In this paper, an Off-Off fluorescence sensor based on ZnS quantum dots was designed. It was found that Co²⁺ can quench the fluorescence of ZnS QDs, moreover glutathione (GSH) can further quench the fluorescence. Therefore, this method can be used for indirect detection of GSH. However, if change Co²⁺ into other metal ions, the system cannot be used to detect GSH indirectly. For direct detection GSH, that is adding GSH without Co²⁺, the fluorescence intensity changes little, while only amino acid or monosaccharide has no effect. When indirect detection of GSH based on this Off-Off fluorescent probe, the fluorescence quenching was linearly related to the concentration range of 1–300 μM GSH, and the detection limit could reach 0.48 μM, which can rival most Off-On and On-Off fluorescent probe. The relative standard deviation for parallel measurement of 300 μmol·L^-1 GSH solution (for n = 10) was 1.43 %.
Role of dietary antioxidants and redox status in Parkinson's disease
2023, Diet and Nutrition in Neurological Disorders
Parkinson's disease (PD) is the second common neurodegenerative age-related disorder. One of the pathologic pathways related to PD is oxidative stress. When the antioxidant capacity against free radicals is low, free oxygen species lead to dopaminergic nerve cell damage. ROS produced through many intracellular and extracellular sources such as mitochondrial dysfunction, iron accumulation, environmental factors such as poisoning, and dietary factors. Therefore, it seems using antioxidants that neutralize free radicals can be effective in curing PD. Several antioxidants such as coenzyme Q10, GSH, and melatonin have been assessed in clinical trials. Some studies showed the beneficial effect of these agents but the results of other works are still insufficient to conclude that they improve nerve damage and clinical symptoms in PD patients. This may be due to the symptoms of PD that occur when a large number of neurons are lost and these antioxidants may not be strong enough to protect the remaining neurons. Therefore, if there would be a marker to identify patients before the onset of symptoms, there will be more success in applying antioxidants to prevent the disease progression. However, more clinical studies with a longer duration can help recognize the beneficial effects of these antioxidants. Herein, we discussed clinical studies that assessed the effect of antioxidant agents on Parkinson's disease.
ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation
2021, Redox Biology
The NLRP3 inflammasome is a multiprotein complex responsible for the maturation of precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines. Increasing evidence suggests that modulation of redox homeostasis contributes to the activation of the NLRP3 inflammasome. However, specific mechanistic details remain unclear. We demonstrate here that ATP exposure evoked a sharp decrease in glutathione (GSH) levels in macrophages, which led to NLRP3 inflammasome activation. We detected an increase in GSH levels in culture supernatants that was comparable to the GSH decrease in macrophages, which suggests that exposure to ATP stimulated GSH efflux. Exogenous addition of P2X7 receptor antagonist, GSH, or the oxidized form GSSG attenuated this efflux. Also, exogenous GSH or GSSG strongly inhibited NLRP3 inflammasome activation in vitro and in vivo. These data suggest that GSH efflux controls NLRP3 inflammasome activation, which may lead to development of novel therapeutic strategies for NLRP3 inflammasome-associated disorders.
Using the Oxytosis/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases
2020, Cell Chemical Biology
Citation Excerpt :
Animal studies have shown that treatment with GSH analogs can reduce the neurodegeneration seen in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of PD in mice (Chinta et al., 2006). More importantly, GSH administration to a small group of PD patients resulted in significant improvements in disability (Sechi et al., 1996). GSH loss has also been noted in the motor cortex in patients with amyotrophic lateral sclerosis (ALS) (Rae and Williams, 2017).
Oxytosis was first described over 30 years ago in nerve cells as a non-excitotoxic pathway for glutamate-induced cell death. The key steps of oxytosis, including glutathione depletion, lipoxygenase activation, reactive oxygen species accumulation, and calcium influx, were identified using a combination of chemical and genetic tools. A pathway with the same characteristics as oxytosis was identified in transformed fibroblasts in 2012 and named ferroptosis. Importantly, the pathophysiological changes seen in oxytosis and ferroptosis are also observed in multiple neurodegenerative diseases as well as in the aging brain. This led to the hypothesis that this pathway could be used as a screening tool to identify novel drug candidates for the treatment of multiple age-associated neurological disorders, including Alzheimer's disease (AD). Using this approach, we have identified several AD drug candidates, one of which is now in clinical trials, as well as new target pathways for AD.
Preventive treatments to slow substantia nigra damage and Parkinson's disease progression: A critical perspective review
2020, Pharmacological Research
Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel drug targets that should be targeted to slow PD progression, and b) clinical and experimental research data reporting new treatments targeting immune-inflammatory and oxidative pathways. A systematic search was performed based on the major databases, i.e., ScienceDirect, Web of Science, PubMed, CABI Direct databases, and Scopus, on relevant studies performed from 1900 to 2020. This review considers the crucial roles of mitochondria and immune-inflammatory and oxidative pathways in the pathophysiology of PD. High levels of oxidative stress in the substantia nigra, as well as modifications in glutathione regulation, contribute to mitochondrial dysfunction, with a decline in complex I of the mitochondrial electron transport chain reported in PD patients. Many papers suggest that targeting antioxidative systems is a crucial aspect of preventive and protective therapies, even justifying the utilization of N-acetylcysteine (NAC) supplementation to fortify the protection afforded by intracellular glutathione. Dietary recommended panels including ketogenetic diet, muscular exercise, nutraceutical supplementation including NAC, glutathione, nicotine, caffeine, melatonin, niacin, and butyrate, besides to nonsteroidal anti-inflammatory drugs (NSAIDs), and memantine treatment are important aspects of PD therapy. The integration of neuro-immune, antioxidant, and nutritional approaches to treatment should afford better neuroprotection, including by attenuating neuroinflammation, nitro-oxidative stress, mitochondrial dysfunction, and neurodegenerative processes. Future research should clarify the efficacy, and interactions, of nicotine receptor agonists, gut microbiome-derived butyrate, melatonin, and NSAIDs in the treatment of PD.

View all citing articles on Scopus

View full text

Full length original paper clinical studyReduced intravenous glutathione in the treatment of early parkinson's disease

Abstract

Neurosci Lett

Biochem Biophys Res Commun

Bloodbrain barrier restriction of peptides and the low uptake of enkephalins

Endocrinology

Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gemirn des Menschen und ihr Verhalten bei Erkrankungen des Extrapyramidalen Systems

Klin Wochenschr.

The protective influence of the locus coeruleus on the blood-brain barrier

Ann Neurol

Altered mitochondrial function, iron metabolism and glutathione levels in Parkinson's disease

Acta Neurol Scand

New insights into the cause of Parkinson's disease

Neurology

Glutathione depletion mimics MPTP neurotoxicity and age-correlated changes in dopamine neurons in substantia nigra of the C 57BL/6NNia mouse

Soc for Neuroscience Abstracts 12

Glutathione and related gamma-glutamyl compounds: biosynthesis and utilization

Ann Rev Biochem

Full length original paper clinical study
Reduced intravenous glutathione in the treatment of early parkinson's disease