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Randomized, Double-Blind, Pilot Evaluation of Intravenous Glutathione in Parkinson's Disease
Abstract
The objective of this study was to evaluate the safety, tolerability, and preliminary efficacy of intravenous glutathione in Parkinson's disease (PD) patients. This was a randomized, placebo-controlled, double-blind, pilot trial in subjects with PD whose motor symptoms were not adequately controlled with their current medication regimen. Subjects were randomly assigned to receive intravenous glutathione 1,400 mg or placebo administered three times a week for 4 weeks. Twenty-one subjects were randomly assigned, 11 to glutathione and 10 to placebo. One subject who was assigned to glutathione withdrew from the study for personal reasons prior to undergoing any postrandomization efficacy assessments. Glutathione was well tolerated and there were no withdrawals because of adverse events in either group. Reported adverse events were similar in the two groups. There were no significant differences in changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores. Over the 4 weeks of study medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more in the glutathione group (P = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 units more in the glutathione group (P = 0.54). Glutathione was well tolerated and no safety concerns were identified. Preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study.
... The overall benefits, while positive, appear limited [19,20]. Fortunately, cell therapy may prove beneficial for restoration of neuronal structure and function [15][16][17]. ...
... Dopaminergic neurons, derived from fetal brain tissue, human embryonic stem cells, human induced pluripotent stem cells, mesenchymal stem cells, medicinal signaling cells, human neural stem cells, direct reprogramming of somatic cells or direct reprogramming stem cells by either gene editing, and/or gene transfer, have elicited keen interest as to the eventual treatment of Parkinson disease. However, thus far, these experimental therapies under development have proved in clinical trials to be of limited therapeutic value [1,4,13,15,17,18,[21][22][23][24][25][26]. ...
... While use of stem cell-derived dopaminergic neurons, derived from fetal brain tissue, human embryonic stem cells, human induced pluripotent stem cells, mesenchymal stem cells, human neural stem cells, direct reprogramming of somatic cells or direct reprogramming stem cells by either gene editing, and/or gene transfer are promising approaches to the eventual treatment of Parkinson disease, these experimental therapies under development, thus far, have proved of limited therapeutic value in clinical trials [1,4,13,15,17,18,[21][22][23][24][25][26][27]. ...
Parkinson disease (PD) is the second most common progressive neurodegenerative disorder that affects older adults. PD is characterized by a low level of dopamine being expressed in the striatum and a deterioration of dopaminergic neurons and associated neural networks in the substantia nigra of the midbrain. Current medical, surgical, and rehabilitative treatments for PD have long-term side effects and do not halt the progression of the disease. Stem cell therapies generating dopaminergic neurons from fetal brain tissue, human embryonic stem cells, human induced pluripotent stem cells, mesenchymal stem cells, human neural stem cells, direct reprogramming of somatic cells and direct reprogramming of stem cells by either gene editing, and/or gene transfer have elicited keen interest as to eventual therapeutics for Parkinson disease. Unfortunately, thus far, these experimental therapies have proved to be of limited therapeutic value in clinical trials. Using a neurotoxin-induced animal model of PD, transplantation of a naïve telomerase positive pluripotent stem cell clone demonstrated reconstitution of dopaminergic neurons and associated neural networks when stereotactically injected into neurotoxin-lesioned substantia nigra pars compactum of the ventral midbrain. Two IRB-approved clinical trials in small cohort studies (n=8 & n=4), with a combined sample size of n=12, demonstrated that intranasal infusion of autologous telomerase positive totipotent cells followed by intravenous infusion of telomerase positive pluripotent stem cells and mesodermal stem cells had a positive influence on patient symptomology with Parkinson’s Disease. No adverse effects were reported by any participant or their respective caregiver for the entire combined small cohort study (n=12). Taken together as a 2021 update of this on-going clinical study, 33% (n=4) showed moderate to no benefit of telomerase positive stem cell treatment by demonstrating a continued decline in symptoms after treatment; 33% (n=4) remained in stasis after the first month after treatment; and 33% (n=4) resolved their symptoms. The results suggest that autologous telomerase positive stem cells, TSCs, PSCs, and MesoSCs, are safe and efficacious (66%) to reduce the symptoms in participants with Parkinson’s disease.
... Therefore, supplementing GSH may effectively improve the symptoms of PD. In recent years, a number of clinical trials have sought to investigate the effects of GSH treatment for PD (10)(11)(12). Regrettably, the sample size of these studies was small and the clinical evidence is insufficient (10)(11)(12). To the best of our knowledge, no previous meta-analyses have assessed the efficacy and safety of GSH in patients with PD. ...
... In recent years, a number of clinical trials have sought to investigate the effects of GSH treatment for PD (10)(11)(12). Regrettably, the sample size of these studies was small and the clinical evidence is insufficient (10)(11)(12). To the best of our knowledge, no previous meta-analyses have assessed the efficacy and safety of GSH in patients with PD. ...
... Pooled results UPDRS. There were five studies reporting data on UPDRS I, II and III (10)(11)(12)14,16). Due to differences in data type (end value and end value minus baseline value), the SMD was applied to determine differences in the UPDRS I, II and III scores between the GSH and control groups. ...
The aim of the present study was to assess the efficacy and safety of glutathione (GSH) for the treatment of Parkinson's disease (PD). The PubMed, Cochrane Library, OvidSP, Web of Science, China Science and Technology Journal Database, Chinese National Knowledge Infrastructure and China Wanfang Standards Database databases were systematically searched from the inception dates to October 1st, 2019, using the key words'glutathione' or 'GSH' and 'Parkinson' or 'Parkinson's disease' or 'PD'. The quality of the included articles was assessed using the bias risk assessment tool of the Cochrane systematic evaluator manual (version 5.1.0). Pooled analysis of the relevant data was performed using RevMan 5.3 software and subgroup analysis was performed to determine the impact of the dosage (300 vs. 600 mg) on the outcome measures. A total of seven randomized controlled trials involving 450 participants were included in the meta-analysis. The results of the present study indicated a statistically significant difference between the GSH and control groups, in terms of the Unified Parkinson's Disease Rating Scale (UPDRS) III [standard mean difference (SMD), -0.48; 95% CI, -(0.88-0.08); P=0.02] and GSH peroxidase (SMD, 1.88; 95% CI, 0.52-3.24; P=0.007). However, the differences in the UPDRS I (SMD, -0.04; 95% CI, -0.25-0.16; P=0.70) and UPDRS II (SMD, 0.03; 95% CI, -0.17-0.24; P=0.77) score and in side effects were not statistically significant between the groups. Subgroup analyses revealed that the dosage (300 vs. 600 mg) was an influencing factor for UPDRS III. The present study demonstrated that GSH may mildly improve motor scores in PD, but not at the expense of increased adverse events.
... Notably, some experimental studies documented that GSH may cross the blood-brain barrier intact by a saturable, low-affinity transport process [29], and in a Sechi et al. study in 1996, the administration of large doses of GSH intravenously to untreated, early PD patients, improved bradykinesia and other PD motor symptoms significantly [30]. In support of this finding, a mild symptomatic effect of lower doses of intravenous GSH on PD motor symptoms in patients not adequately controlled with their current medication was shown by Hauser et al. in 2009, in a randomised controlled trial [31]. ...
... Notably, some experimental studies documented that GSH may cross the blood-brain barrier intact by a saturable, low-affinity transport process [29], and in a Sechi et al. study in 1996, the administration of large doses of GSH intravenously to untreated, early PD patients, improved bradykinesia and other PD motor symptoms significantly [30]. In support of this finding, a mild symptomatic effect of lower doses of intravenous GSH on PD motor symptoms in patients not adequately controlled with their current medication was shown by Hauser et al. in 2009, in a randomised controlled trial [31]. ...
Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders.
... Notably, some experimental studies documented that GSH may cross the blood-brain barrier intact by a saturable, low-affinity transport process [29], and in a Sechi et al. study in 1996, the administration of large doses of GSH intravenously to untreated, early PD patients, improved bradykinesia and other PD motor symptoms significantly [30]. In support of this finding, a mild symptomatic effect of lower doses of intravenous GSH on PD motor symptoms in patients not adequately controlled with their current medication was shown by Hauser et al. in 2009, in a randomised controlled trial [31]. ...
... Notably, some experimental studies documented that GSH may cross the blood-brain barrier intact by a saturable, low-affinity transport process [29], and in a Sechi et al. study in 1996, the administration of large doses of GSH intravenously to untreated, early PD patients, improved bradykinesia and other PD motor symptoms significantly [30]. In support of this finding, a mild symptomatic effect of lower doses of intravenous GSH on PD motor symptoms in patients not adequately controlled with their current medication was shown by Hauser et al. in 2009, in a randomised controlled trial [31]. ...
Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders.
... Targeting astroglial-mediated functions A randomized, double-blind, pilot evaluation of intravenous glutathione in PD was conducted (n = 21). 112 Although glutathione was well tolerated, no clinical benefit for patients with PD was observed due to its low permeability across the BBB. 112 Zonisamide, an epileptic drug, was found to increase GSH production by astrocytes and reduce ...
... 112 Although glutathione was well tolerated, no clinical benefit for patients with PD was observed due to its low permeability across the BBB. 112 Zonisamide, an epileptic drug, was found to increase GSH production by astrocytes and reduce ...
Astrocytes are abundantly and ubiquitously expressed cell types with diverse functions throughout the central nervous system. Astrocytes show remarkable plasticity and exhibit morphological, molecular, and functional remodeling in response to injury, disease, or infection of the central nervous system, as evident in neurodegenerative diseases. Astroglial mediated inflammation plays a prominent role in the pathogenesis of neurodegenerative diseases. This review focus on the role of astrocytes as essential players in neuroinflammation and discuss their morphological and functional heterogeneity in the normal central nervous system and explore the spatial and temporal variations in astroglial phenotypes observed under different disease conditions. This review discusses the intimate relationship of astrocytes to pathological hallmarks of neurodegenerative diseases. Finally, this review considers the putative therapeutic strategies that can be deployed to modulate the astroglial functions in neurodegenerative diseases.
Highlights
Astroglia mediated neuroinflammation plays a key role in the pathogenesis of neurodegenerative diseases.
Activated astrocytes exhibit diverse phenotypes in a region‐specific manner in brain and interact with β‐amyloid, tau, and α‐synuclein species as well as with microglia and neuronal circuits.
Activated astrocytes are likely to influence the trajectory of disease progression of neurodegenerative diseases, as determined by the stage of disease, individual susceptibility, and state of astroglial priming.
Modulation of astroglial activation may be a therapeutic strategy at various stages in the trajectory of neurodegenerative diseases to modify the disease course.
... The first one showed symptomatic efficacy with two daily GSH doses of 600 mg for 30 days in a small group of newly diagnosed and untreated PD patients (Table 3) [113]. In the second study, PD patients whose motor symptoms were not well controlled with their medication regimen were subjected to GSH doses of 1400 mg three times a week for four weeks [114], finding that GSH was welltolerated and safe and suggesting the possibility of a slight symptomatic effect. However, both studies' symptomatic improvements should be verified in a more extensive study with more subjects to detect significant differences. ...
... Glutathione Pilot evaluation Phase I 9 GSH has symptomatic effects and possibly retards the progression of the disease [113] Randomized, Double-Blind, Pilot Evaluation Phase I 11 + 10 Safe and well-tolerated [114] Randomized, double-blind Phase I/IIa 15 + 15 ...
Oxidative stress is considered one of the pathological mechanisms that cause Parkinson’s disease (PD), which has led to the investigation of several antioxidants molecules as a potential therapeutic treatment against the disease. Although preclinical studies have demonstrated the efficacy of these compounds to maintain neuronal survival and activity in PD models, these results have not been reflected in clinical trials, antioxidants have not been able to act as disease modifiers in terms of clinical symptoms. Translational medicine currently faces the challenge of redesigning clinical trials to standardize criteria when testing molecules to reduce responses’ variability. Herein, we discuss current challenges and opportunities regarding several non-enzymatic antioxidants’ therapeutic molecules for PD patients’ potential treatment.
... However, the GSH depletion could be caused by impaired synthesis of GSH, which is a result of mitochondrial dysfunction since there is not an adequate quantity of ATP to sustain the GSH production [43,44]. To support this hypothesis, Hauser et al. [45] proved that GSH is reduced approximately 40-50% in PD patients. Figure 1: Parkinson's disease mechanism of action in the central nervous system and the pharmacokinetic effects of several agents that induce Parkinson-like symptoms. ...
... Due to the fact that the participants to this mechanism are highly conserved, OS induction in this way was observed in zebrafish, mice, rats, cats, dogs, and nonhuman primates [35,85]. In zebrafish, the reports showed that MPTP could efficiently induce decreased locomotor activity, which is caused by DA activity decrease, number of DA neurons, and pretectal size reduction [45,49,[86][87][88]. Also, MPTP could induce bradykinesia manifested in zebrafish as decreased velocity and abnormal swimming behaviour [49,86,89]. ...
The complex yet not fully understood pathophysiology of Parkinson's disease includes an important molecular component consisting of oxidative status changes, thus leading to oxidative stress occurrence. While no particular evidence has been reported that describes the relationship between oxidative stress and the molecular mechanisms behind Parkinson's disease development, animal model studies has shown that oxidative stress induction could modulate Parkinson's disease symptomatology. Despite the inability to perfectly replicate human disease in animals and despite that Parkinson's disease has not been reported in any animal species, animal modeling is one of the most important tools in understanding the complex mechanisms of human disorders. In this way, this study is aimed at detailing this particular relationship and describing the molecular mechanisms underlying Parkinson's disease in animal models, focusing on the potential advantages and disadvantages of zebrafish in this context. The information relevant to this topic was gathered using major scientific database research (PubMed, Google Scholar, Web of Science, and Scopus) based on related keywords and inclusion criteria. Thus, it was observed that oxidative stress possesses an important role in Parkinson's disease as shown by numerous animal model studies, many of which are based on rodent experimental models. However, an emerging impact of the zebrafish model was observed in the research of Parkinson's disease pathological mechanisms with regard to disease development factors and the cause-effect relationship between oxidative stress and comorbidities (such as depression, hyposmia, fatigue, sleep disturbances, and cognitive deficits) and also with regard to the pharmacological potential of antioxidant molecules in Parkinson's disease treatment.
... Treatment with glutathione's precursor N-acetylcysteine (NAC) prevents oxidative stress and calcium overload and rescues neurons and other brain cells during PD-like stress [102,112,135]. Consistently, a protective effect of intravenous and oral delivery of NAC has been reported in PD patients [199][200][201]; NAC is naturally found in onions and garlic, and it is available in various dosages as an over-the-counter dietary supplement [202]. However, the best duration and concentration of supplementation to consistently show a therapeutic effect in humans has not been established [200,203]. ...
... Consistently, a protective effect of intravenous and oral delivery of NAC has been reported in PD patients [199][200][201]; NAC is naturally found in onions and garlic, and it is available in various dosages as an over-the-counter dietary supplement [202]. However, the best duration and concentration of supplementation to consistently show a therapeutic effect in humans has not been established [200,203]. Therefore, further investigation is required. Additionally, since oral glutathione is less bioavailable, finding nutrients that enhance the body's ability to synthesize glutathione may also be of benefit. ...
Parkinson’s disease (PD) is a neurodegenerative disorder caused by the depletion of dopaminergic neurons in the basal ganglia, the movement center of the brain. Approximately 60,000 people are diagnosed with PD in the United States each year. Although the direct cause of PD can vary, accumulation of oxidative stress-induced neuronal damage due to increased production of reactive oxygen species (ROS) or impaired intracellular antioxidant defenses invariably occurs at the cellular levels. Pharmaceuticals such as dopaminergic prodrugs and agonists can alleviate some of the symptoms of PD. Currently, however, there is no treatment to halt the progression of PD pathology. Due to the nature of PD, a long and progressive neurodegenerative process, strategies to prevent or delay PD pathology may be well suited to lifestyle changes like dietary modification with antioxidant-rich foods to improve intracellular redox homeostasis. In this review, we discuss cellular and genetic factors that increase oxidative stress in PD. We also discuss neuroprotective roles of dietary antioxidants including vitamin C, vitamin E, carotenoids, selenium, and polyphenols along with their potential mechanisms to alleviate PD pathology.
... In another study, PD patients with badly controlled motor symptoms were intravenously administrated 1400 mg of glutathione three times a week for four weeks. The outcome was a minor symptomatic improvement and well-tolerated glutathione (Hauser et al. 2009). Regardless of the limited success shown in these two studies, further investigations with more subjects and optimized doses to observe more significant improvements in patients are necessary to conduct. ...
A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or “good stress” and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2–related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress (“bad stress”). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer’s and Parkinson’s diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.
... Glutathione, another antioxidant known to be significantly reduced in the brain of PD patients, and considered 'generally recognized as safe' by the FDA, also failed to show efficacy in a 12-week phase II study evaluating thrice-weekly dosing of intravenous glutathione compared to placebo [185]. While there may be a beneficial effect if the problem of blood-brain barrier permeability could be overcome, we must agree with other pre-eminent leaders in the field who suggest "patients with PD should be encouraged to say no to an IV placed in their arm for the false hope of a symptomatic glutathione treatment" [186]. ...
As the prevalence of Parkinson's disease (PD) grows, so too does the population at-risk of developing PD, those in the so-called prodromal period. This period can span from those experiencing subtle motor deficits yet not meeting full diagnostic criteria or those with physiologic markers of disease alone. Several disease-modifying therapies have failed to show a neuroprotective effect. A common criticism is that neurodegeneration, even in the early motor stages, has advanced too far for neuro-restoration-based interventions to be effective. Therefore, identifying this early population is essential. Once identified, these patients could then potentially benefit from sweeping lifestyle modifications to alter their disease trajectory. Herein, we review the literature on risk factors for, and prodromal symptoms of, PD with an emphasis on ones which may be modifiable in the earliest possible stages. We propose a process for identifying this population and speculate on some strategies which may modulate disease trajectory. Ultimately, this proposal warrants prospective studies.
... Based on biological plausibility and pre-clinical evidence of potential benefit [10][11][12], several dietary supplements have been formally studied in PD clinical trials, such as coenzyme Q10 [13][14][15], creatine [16,17], glutathione [18][19][20], N-acetyl cysteine (NAC) [21] and nicotinamide [22]. The results have been mixed in randomized clinical trials, suggesting either true non-efficacy of nutraceuticals or that our pre-clinical models, traditional outcome measures, and/or study designs are flawed. ...
Background:
It is estimated that half of the individuals with Parkinson's disease (PD) use some form of over-the-counter vitamin, herbal supplement or nutraceutical. The goal of this study was to survey individuals with PD about their use of the nutraceuticals and evaluate the association of the nutraceutical with the severity of symptoms.
Methods:
Participants with self-reported idiopathic PD within the 2021 cohort (n = 1084) were included in a cross-sectional study to assess association of nutraceuticals with symptom severity via linear regression analysis. PD severity was measured using the patient-reported outcomes in PD, and supplement use reflected self-reported consistent use over the previous six months. All regression analyses adjusted for age, gender, income and years since diagnosis. The use of the term progression refers to PRO-PD scores adjusted for years since diagnosis.
Results:
The most frequently used supplements were vitamin D (71%), B12 (44%), vitamin C (38%) and fish oil (38%). None of the supplements being used were associated with statistically significant worse outcomes. Nutraceuticals associated with improved outcomes were Ginkgo biloba (GB), NAD+ or its precursors, 5-methyltetrahydrofolate, glutathione, mucuna, CoQ10, low dose lithium, curcumin, homocysteine factors, DHEA, coconut oil, vitamin C, and omega-3 fatty acids (fish oil).
Conclusions:
These data suggest that in a real-world setting, some over-the-counter supplements are associated with fewer patient-reported symptoms. Supplements with significant associations with fewer symptoms have biological plausibility and future clinical trials should be explored.
... In one study, impaired mitochondrial function and GSH depletion are the earliest known indicators of substantia nigra degeneration in the brain of PD patients, and the magnitude of GSH depletion mimicked the severity of the disease (Jenner, 1998). Links between GSH deficiency and PD have stimulated research on approaches to maintain or restore GSH levels in these patients (Hauser et al., 2009). In particular, the use of N-acetyl cysteine (NAC), the Nacetyl derivative of cysteine, in PD has been proposed to increase cysteine availability and, thus, glutathione synthesis. ...
Parkinson's disease (PD), an age-dependent neurodegenerative disease, is characterised by the selective loss of dopaminergic neurons in the substantia nigra (SN). Mitochondrial dysfunction is a hallmark of PD, and mutations in PINK1, a gene necessary for mitochondrial fitness, cause PD. Drosophila melanogaster flies with pink1 mutations exhibit mitochondrial defects and dopaminergic cell loss and are used as a PD model. To gain an integrated view of the cellular changes caused by defects in the PINK1 pathway of mitochondrial quality control, we combined metabolomics and transcriptomics analysis in pink1-mutant flies with human induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) with a PINK1 mutation. We observed alterations in cysteine metabolism in both the fly and human PD models. Mitochondrial dysfunction in the NPCs resulted in changes in several metabolites that are linked to cysteine synthesis and increased glutathione levels. We conclude that alterations in cysteine metabolism may compensate for increased oxidative stress in PD, revealing a unifying mechanism of early-stage PD pathology that may be targeted for drug development.
This article has an associated First Person interview with the first author of the paper.
... A phase IIb study investigated the effect of intranasal GSH in 45 patients with PD and demonstrated improvement in motor function over baseline (NCT02424708) [187]. In addition, other small clinical trials testing GSH and the GSH precursor NAC in PD have also demonstrated symptomatic improvement [187][188][189]. However, there are some other clinical trials on GSH use in patients with PD that have shown inconclusive or negative results ( Table 2). ...
Parkinson disease (PD) is the second-most common neurodegenerative disease. The characteristic pathology of progressive dopaminergic neuronal loss in people with PD is associated with iron accumulation and is suggested to be driven in part by the novel cell death pathway, ferroptosis. A unique modality of cell death, ferroptosis is mediated by iron-dependent phospholipid peroxidation. The mechanisms of ferroptosis inhibitors enhance antioxidative capacity to counter the oxidative stress from lipid peroxidation, such as through the system xc−/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis and the coenzyme Q10 (CoQ10)/FSP1 pathway. Another means to reduce ferroptosis is with iron chelators. To date, there is no disease-modifying therapy to cure or slow PD progression, and a recent topic of research seeks to intervene with the development of PD via regulation of ferroptosis. In this review, we provide a discussion of different cell death pathways, the molecular mechanisms of ferroptosis, the role of ferroptosis in blood–brain barrier damage, updates on PD studies in ferroptosis, and the latest progress of pharmacological agents targeting ferroptosis for the intervention of PD in clinical trials.
... This difference in response may be attributed to the high degradation rate of GSH in the gastrointestinal tract resulting in lowered concentration in CSF (Witschi et al. 1992). To overcome this problem, GSH was administered intravenously to PD patients in two separate clinical trials wherein GSH was found to be well tolerated and safe suggesting the possibility of a symptomatic effect (Sechi et al. 1996;Hauser et al. 2009). In an effort to figure out alternative routes of GSH administration, non-invasive intranasal delivery was also tested. ...
As conventional therapeutics can only treat the symptoms of Parkinson's disease (PD), major focus of research in recent times is to slow down or prevent the progression of neuronal degeneration in PD. Non-targeted antioxidants have been an integral part of the conventional therapeutics regimen; however, their importance have lessened over time because of their controversial outcomes in clinical PD trials. Inability to permeate and localize within the mitochondria remains the main drawback on the part of non-targeted antioxidants inspite of possessing free radical scavenging properties. In contrast, mitochondrial-targeted antioxidants (MTAs), a special class of compounds have emerged having high advantages over non-targeted antioxidants by virtue of efficient pharmacokinetics and better absorption rate with capability to localize many fold inside the mitochondrial matrix. Preclinical experimentations indicate that MTAs have the potential to act as better alternatives compared to conventional non-targeted antioxidants in treating PD; however, sufficient clinical trials have not been conducted to investigate the efficacies of MTAs in treating PD. Controversial clinical outcomes on the part of non-targeted antioxidants and lack of clinical trials involving MTAs have made it difficult to go ahead with a direct comparison and in turn have slowed down the progress of development of safer and better alternate strategies in treating PD. This review provides an insight on the roles MTAs and non-targeted antioxidants have played in the treatment of PD till date in preclinical and clinical settings and discusses about the limitations of mitochondria-targeted and non-targeted antioxidants that can be resolved for developing effective strategies in treating Parkinsonism.
... While the intravenous administration of 1200 mg/day of reduced glutathione was shown to significantly improve disability [430], a subsequent trial with 700 mg glutathione/day given also IV failed to confirm these results [431]. After a phase 1 safety trial (NCT01398748), intranasally administered glutathione was tested in a phase 2b study on 45 participants over 12 weeks for efficacy on disease progression ((in) GSH, NCT02424708) but showed null results [432]. Studies with other dietary antioxidants are in preclinical phases, but, considering the poor BBB penetration of these compounds [433], it is unlikely that they will successfully translate in clinical settings. ...
As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.
... As mentioned above, GSH supplementation would be a plausible approach to protect oxidative stress-induced dopaminergic neurodegeneration. However, direct intravenous chronic injections of relatively high doses of GSH showed no significant ameliorating effects on motor symptoms of PD patients [76], because GSH is unstable and easily degradable to amino acids by peripheral peptidase. Another approach of intranasal GSH treatment was examined [77]. ...
Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis, and release in/from surrounding astrocytes. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a detoxifying master transcription factor, is expressed mainly in astrocytes and activates the gene expression of various phase II drug-metabolizing enzymes or antioxidants including GSH-related molecules and metallothionein by binding to the antioxidant response element (ARE) of these genes. Accumulating evidence has shown the involvement of dysfunction of antioxidative molecules including GSH and its related molecules in the pathogenesis of Parkinson’s disease (PD) or parkinsonian models. Furthermore, we found several agents targeting GSH synthesis in the astrocytes that protect nigrostriatal dopaminergic neuronal loss in PD models. In this article, the neuroprotective effects of supplementation and enhancement of GSH and its related molecules in PD pathology are reviewed, along with introducing new experimental findings, especially targeting of the xCT-GSH synthetic system and Nrf2–ARE pathway in astrocytes.
... À ce jour, aucun antagoniste spécifique de ce canal n'existe, en revanche, des modulateurs de faible affinité comme par exemple l'isradipine, sont actuellement en essai clinique de phase III (Biglan et al., 2017). En plus de cette inhibition calcique, ce stress oxydatif peut être directement diminué en augmentant notamment les niveaux d'antioxydants tels que le N-acetylcystéine (NAC) (NCT01470027) (Katz et al., 2015), l'urate (Gong et al., 2012) ou le glutathion (NCT02424708, NCT01470027) (Hauser et al., 2009) ou en diminuant les niveaux de fer (Das et al., 2017). ...
La maladie de Parkinson (MP) est caractérisée essentiellement par la perte progressive des neurones dopaminergiques (DA) de la substance noire parse compacte (SNpc) qui innervent le striatum et contrôlent les mouvements volontaires. Une des approches thérapeutiques de la MP est la transplantation ectopique de précurseurs DA fœtaux issus du mésencéphale ventral (MV) dans le striatum. Il est peu probable que la transplantation des neurones DA du MV humain devienne un traitement de routine de la MP en raison de problèmes d’approvisionnement et de standardisation de tissus pour la transplantation. L’avenir de ces greffes dépend donc de l’obtention de sources alternatives de tissus. L’objectif de ce projet est d’obtenir des neurones DA issus de cellules souches embryonnaires de souris et d’évaluer leur potentiel thérapeutique en les greffant dans le striatum ou la SN dans un modèle murin de la MP. Afin d’augmenter le nombre de neurones DA du type nigral, l’expression de LMX1A, un facteur de transcription jouant un rôle clé dans le développement embryonnaire des progéniteurs des neurones DA du MV, a été forcée. Nous avons montré que, in vitro, LMX1A induit une augmentation de précurseurs et de neurones DA du type nigral. Après transplantation dans la SN ou le striatum, les cellules survivent, expriment des marqueurs de neurones DA du type nigral et projettent vers le striatum. L’expression forcée de LMX1A semble augmenter, in vivo, la proportion de neurones DA matures responsables d’une réduction des déficits moteurs après transplantation dans le striatum.
... As a result, there was an improvement in motor scores in the glutathione group when compared to the placebo group. There were no reports of adverse events associated with the use of glutathione in this study (60). In 2020, Horowitz and collaborators published a study evaluating the use of oral / intravenous glutathione in the treatment of patients with dyspnea associated with COVID-19-related pneumonia. ...
... Depleted glutathione can cause nigral dopaminergic neuronal death and progressive motor imbalance [149]. Clinical trials showed that glutathione level was restored following glutathione administration, indicating its mild therapeutic effect in PD patients [150,151]. GPX4, an important lipid repair enzyme in the inhibition of ferroptosis, was reduced in the SNc of deceased PD patients, while its up-regulation was associated with neuron density [152]. Ablation of glutathione by depleting intracellular cysteine levels with erastin treatment, suppressing glutathione availability as a substrate for GPX4, could induce ferroptosis [46,55]. ...
Rapid increase in aging populations is an urgent problem because older adults are more likely to suffer from disabilities and age-related diseases (ARDs), burdening healthcare systems and society in general. ARDs are characterized by the progressive deterioration of tissues and organs over time, eventually leading to tissue and organ failure. To date, there are no effective interventions to prevent the progression of ARDs. Hence, there is an urgent need for new treatment strategies. Ferroptosis, an iron-dependent cell death, is linked to normal development and homeostasis. Accumulating evidence, however, has highlighted crucial roles for ferroptosis in ARDs, including neurodegenerative and cardiovascular diseases. In this review, we a) summarize initiation, regulatory mechanisms, and molecular signaling pathways involved in ferroptosis, b) discuss the direct and indirect involvement of the activation and/or inhibition of ferroptosis in the pathogenesis of some important diseases, and c) highlight therapeutic targets relevant for ARDs. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
... It is comprised largely of three amino acids: glutamine, glycine, and cysteine [23]. High levels of glutathione in body cells is associated with numerous health benefits such as support of immune function, making of DNA, formation of sperm cells, breaking down free radicals, assisting in apoptosis, increase in insulin resistance in aged people, wound healing and reduction in the symptoms of Parkinson's disease amongst other notable profits [23][24][25]. Furthermore, low levels of glutathione has been linked with several diseases such as Parkinson's disease, autoimmune diseases, Alzheimer's disease, several heart complications and chronic kidney diseases [26]. ...
... PD patients with intravenous infusion of GSH (1200 mg/d) demonstrates 42% decline in disability compared to vehicle-treated controls [267]. However, another study shows no significant PD improvement by intravenous administration of GSH (700 mg/d) ( Table 2) [268]. A larger randomized, double-blind, placebo-controlled trial on 45 PD patients shows intranasal GSH administration (300 or 600 mg/d) displays PD improvement similar to placebo [269]. ...
Parkinson’s disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra (SN). Studies have suggested the potential involvement of dopamine, iron, calcium, mitochondria and neuroinflammation in contributing to overwhelmed oxidative stress and neurodegeneration in PD. Function studies on PD-causative mutations of SNCA, PRKN, PINK1, DJ-1, LRRK2, FBXO7 and ATP13A2 further indicate the role of oxidative stress in the pathogenesis of PD. Therefore, it is reasonable that molecules involved in oxidative stress, such as DJ-1, coenzyme Q10, uric acid, 8-hydroxy-2’-deoxyguanosin, homocysteine, retinoic acid/carotenes, vitamin E, glutathione peroxidase, superoxide dismutase, xanthine oxidase and products of lipid peroxidation, could be candidate biomarkers for PD. Applications of antioxidants to modulate oxidative stress could be a strategy in treating PD. Although a number of antioxidants, such as creatine, vitamin E, coenzyme Q10, pioglitazone, melatonin and desferrioxamine, have been tested in clinical trials, none of them have demonstrated conclusive evidence to ameliorate the neurodegeneration in PD patients. Difficulties in clinical studies may be caused by the long-standing progression of neurodegeneration, lack of biomarkers for premotor stage of PD and inadequate drug delivery across blood–brain barrier. Solutions for these challenges will be warranted for future studies with novel antioxidative treatment in PD patients.
... Augmentation of oxidative stress has been implicated in the pathogenesis and progression of various hepatic diseases; therefore, sufficient GSH status and its related antioxidant enzyme activities are necessary to protect oxidative damage in the liver. The efficacy of GSH supplementation has been reported in various diseases, including cystic fibrosis, peripheral obstructive arterial disease, Parkinson's disease, and autism spectrum disorders [35][36][37][38]. Different routes of administration, such as intravenous, inhaled, or oral, have been utilized. ...
Vitamin B-6 and glutathione (GSH) are antioxidant nutrients, and inadequate vitamin B-6 may indirectly limit glutathione synthesis and further affect the antioxidant capacities. Since liver cirrhosis is often associated with increased oxidative stress and decreased antioxidant capacities, we conducted a double-blind randomized controlled trial to assess the antioxidative effect of vitamin B-6, GSH, or vitamin B-6/GSH combined supplementation in cirrhotic patients. We followed patients after the end of supplementation to evaluate the association of vitamin B-6 and GSH with disease severity. In total, 61 liver cirrhosis patients were randomly assigned to placebo, vitamin B-6 (50 mg pyridoxine/d), GSH (500 mg/d), or B-6 + GSH groups for 12 weeks. After the end of supplementation, the condition of patient’s disease severity was followed until the end of the study. Neither vitamin B-6 nor GSH supplementation had significant effects on indicators of oxidative stress and antioxidant capacities. The median follow-up time was 984 d, and 21 patients were lost to follow-up. High levels of GSH, a high GSH/oxidized GSH ratio, and high GSH-St activity at baseline (Week 0) had a significant effect on low Child–Turcotte–Pugh scores at Week 0, the end of supplementation (Week 12), and the end of follow-up in all patients after adjusting for potential confounders. Although the decreased GSH and its related enzyme activity were associated with the severity of liver cirrhosis, vitamin B-6 and GSH supplementation had no significant effect on reducing oxidative stress and increasing antioxidant capacities.
... Other routes of delivery, such as intravenous, intranasal, and sublingual administration, have been suggested as possible alternatives to bypass the issue of gastrointestinal GSH metabolism. Intravenous administration of 1200 mg of GSH daily for 4 weeks or 1400 mg of GSH 3 times a week for 4 weeks resulted in a marked improvement in motor scores in Parkinson's patients, though GSH levels in the brain were not measured (Sechi et al., 1996;Hauser et al., 2009). Intranasal delivery of 200 mg of GSH to Parkinson's patients through a nasal spray increased GSH levels in the brain, as measured by 1 H-MRS 1 h after delivery (Mischley et al., 2016). ...
The mammalian brain has high energy demands, which may become higher in response to environmental challenges such as psychogenic stress exposure. Therefore, efficient neutralization of reactive oxygen species that are produced as a by-product of ATP synthesis is crucial for preventing oxidative damage and ensuring normal energy supply and brain function. Glutathione (GSH) is arguably the most important endogenous antioxidant in the brain. In recent years, aberrant GSH levels have been implicated in different psychiatric disorders, including stress-related psychopathologies. In this review, we examine the available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Additionally, we identify several promising compounds that could raise GSH levels in the brain by either increasing the availability of its precursors or the expression of GSH-regulating enzymes through activation of Nuclear factor erythroid-2-related factor 2 (Nrf2). Given the high tolerability and safety profile of these compounds, they may represent attractive new opportunities to complement existing therapeutic manipulations against stress-related psychopathologies.
... These supplements have been applied both orally and intravenously. 19 GSH is a thiol-containing compound. Its mechanism of action was inferred from past studies that linked thiol-containing compounds (kojic acid, arbutin, hydroquinone) to skin lightening. ...
The skin bleaching industry is a global business with a vast array of anti-melanogenic choices including glutathione. Glutathione is synthesized in vivo but has been used as a bodily supplement by medical personnel to aid in preventative medicine. Known for its antioxidant properties, glutathione has been used for its anti-melanogenic effects. Intravenous glutathione requires more investigation to determine its safety for usage. It continues to be distributed to the cosmetic industry despite antagonism from the Philippine FDA. This study will research the potential effects of intravenous glutathione on women and it will propose the biochemical mechanisms of glutathione in induced disease states in women. The aim is to educate people about safer methods for skin lightening.
Keywords: skin lightening, intravenous glutathione, pheomelanin, Fitzpatrick skin types, Stevens-Johnson syndrome.
Parkinson disease (PD) is the second most common neurodegenerative disease, and its incidence is climbing every year, but there is still a lack of effective clinical treatments. In recent years, many studies have shown that ferroptosis plays a key role in the progression of PD. Most importantly, many cellular and animal studies and clinical trials have shown that episodes of PD can be alleviated by inhibiting the ferroptosis process, such as utilizing inhibitors, chelating agents, and others. Here, we review the role of ferroptosis, a new form of cell death, in the pathogenesis of PD, and summarize the therapeutic strategies for targeting ferroptosis in PD, hoping to provide new thinking for the study of PD pathogenesis and the development of therapeutic strategies.
There is no question that the quantity of food and milk consumed, in addition to the relative abundance of nutrients in the diet, has an effect on brain function. There is currently a considerable body of research suggesting that proper nutrition in one's diet can help in neurologic symptoms treatment and prevention of pathological disorders variety. Important processes responsible for nutrients' impact on brain health include dietary factors on mitochondrial dysfunction, modification of epigenetics, and neuroinflammation. In this chapter, we discuss dietary intervention evidence, such as dietary supplementation that can potent neurological disorders treatment, for example, therapeutic response. In conclusion, also, an innovative hypothesis is that dietary nutritional supplementation can repair brain dysfunction by reshaping the metabolism-epigenetics-immunity loop. Targeting metabolism, a new strategy for overcoming neurological deficiencies will be outlined by the epigenetics-immunity network.
The drug discovery pipelines require enormous time and cost, albeit their infamously high risk of failures. Reducing such risk has therefore been the utmost goal in the process. Recently, natural products (NPs) in traditional oriental medicine (TOM) have come into the spotlight for their efficacy and safety supported throughout the history. Not only that, with the ever-increasing repository of various biological datasets, many data-driven in silico approaches have also been extensively studied for better efficient search and testing. However, TOM-based datasets lack information on recently prevalent diseases, while experimental datasets are prone to provide target spaces that are too large. Adequate combination of both approaches can therefore fill in each other's blanks. In this study, we introduce NaCTR, an in silico discovery pipeline that achieves such integration to suggest NPs-derived drug candidates for a given disease. First, phenotypes and disease genes for the disease are identified in literature and public databases. Secondly, a pool of potentially therapeutic NPs are identified based on both TOM-based phenotype records and compound-gene interaction datasets. Lastly, the compounds contained in the NPs are further screened for toxicity and pharmacokinetic properties. We use the Parkinson's disease as the case study to test the NaCTR pipeline. Through the pipeline, we propose glutathione and four other compounds as novel drug candidates. We further highlight the finding with literature support. As the first to effectively combine data from ancient and recent repositories, the NaCTR pipeline can be a novel pipeline that can be applied successfully to any other diseases.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder globally, significantly affecting the quality of life of affected individuals. Systemic drug delivery to the brain is inefficient because of first‐pass metabolism, the blood‐brain barrier (BBB), and the blood‐cerebrospinal fluid barrier. This inefficiency necessitates increased dosage as the disease progresses, leading to severe side effects that compromise the efficacy of the medication. Nose‐to‐brain (N2B) administration bypasses the BBB, allowing delivery of both small molecules and large protein substances to the central nervous system. Compared with systemic administration, this method enhances brain bioavailability, reduces enzymatic degradation, and minimizes systemic adverse reactions. However, the N2B delivery system is associated with several critical challenges, including mucociliary clearance, enzymatic degradation, and drug translocation via efflux mechanisms. This paper provides a comprehensive overview of the current research progress in intranasal treatment of PD, considering both preclinical and clinical studies, and discusses the physiological aspects and limitations of its delivery system.
Glutathione, a tripeptide consisting of cysteine, glycine, and glutamic acid is present in high level in most human cells. The cellular concentration of glutathione is similar to that of glucose, potassium, and cholesterol. Reactive oxygen species are associated with cell damage in a variety of conditions and disorders. Therefore, they have to be scavenged by antioxidants. Reduced glutathione has been increasingly considered as the most potent intracellular antioxidant. However, low levels of reduced glutathione has been observed in a variety of clinical conditions Therefore, effectively restoring the effective intracellular level of glutathione with the use of parenteral glutathione to serves as an adjuvant therapy in a variety of conditions has been increasingly reported.
The creation of a new electrochemical sensing platform copper metal-organic framework (Cu-MOF) heterostructure is described in this paper. Drop-casting Cu-MOF suspension onto the electrode surface primed the sensor for glutathione...
Genetics, age, environmental factors, and oxidative stress have all been implicated in the development of Parkinson's disease (PD); however, a complete understanding of its pathology remains elusive. At present, there is no cure for PD, and currently available therapeutics are insufficient to meet patient needs. Ferroptosis, a distinctive iron-dependent cell death mode characterized by lipid peroxidation and oxidative stress, has pathophysiological features similar to those of PD, including iron accumulation, reactive oxygen species-induced oxidative damage, and mitochondrial dysfunction. Ferroptosis has been identified as a specific pathway of neuronal death and is closely related to the pathogenesis of PD. Despite the similarities in the biological targets involved in PD pathogenesis and ferroptosis, the relationship between novel targets in PD and ferroptosis has been neglected in the literature. In this review, the mechanism of ferroptosis is discussed, and the potential therapeutic targets implicated in both PD and ferroptosis are compared. Furthermore, the anti-PD effects of several ferroptosis inhibitors, as well as clinical studies thereof, and the identification of novel lead compounds for the treatment of PD and the inhibition of ferroptosis are reviewed. It is hoped that this review can promote research to further elucidate the relationship between ferroptosis and PD and provide new strategies for the development of novel ferroptosis-targeting PD therapy.
ÖZET
Glutatyon; glutamat, sistein ve glisin olmak üzere üç amino asitten oluşan bir tripepttirdir ve biyolojik sistemlerde esas olarak antioksidan olarak görev almaktadır. Glutatyonun antioksidan etkilerine ek olarak melanin oluşumunu engellediği için beşerî hekimlikte ten renginin beyazlatılmasında kullanılmaktadır. Glutatyonun lokal ve oral formülasyonları bulunmaktadır. Bu ticari formlar hakkında sınırlı bilgi bulunmaktadır. Oral formülasyonlarının biyoyarlanımının düşük olması istenilen etkinin oluşma süresini uzatması nedeniyle hızlı etki amacıyla glutatyonun damar içi kullanımı tercih edilmektedir. Ancak ilacın damar içi kullanımı hakkında çok kısıtlı bilgi bulunmaktadır. Bu derleme glutatyon kullanımı, etkileri ve yan etkileri hakkında bilgiler verilmeye çalışılmıştır.
Anahtar kelimeler: Glutatyon, klinik kullanım, yan etki
ABSTRACT
Glutathione a tripeptide consisting of three amino acids, glutamate, cysteine and glycine, and functions mainly as an antioxidant in biological systems. In addition to the antioxidant effects of glutathione, it is used in human medicine for skin whitening because it prevents the formation of melanin. There are topical and oral formulations of glutathione. Limited information is available on these commercial forms. Intravenous use of glutathione is preferred for rapid effect, since the low bioavailability of oral formulations prolongs the time for the desired effect to occur. However, there is very limited information about the intravenous use of the drug. In this review, information about the use of glutathione, its effects and side effects has been tried to be given.
Keywords: Glutathione, clinival usage, side effects
Parkinson's disease (PD) is caused by the progressive loss of dopaminergic cells in substantia nigra pars compacta (SNc). The root cause of this cell loss in PD is still not decisively elucidated. A recent line of thinking has traced the cause of PD neurodegeneration to metabolic deficiency. Levodopa (L-DOPA), a precursor of dopamine, used as a symptom-relieving treatment for PD, leads to positive and negative outcomes. Several researchers inferred that L-DOPA might be harmful to SNc cells due to oxidative stress. The role of L-DOPA in the course of the PD pathogenesis is still debatable. We hypothesize that energy deficiency can lead to L-DOPA-induced toxicity in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a systems-level computational model of SNc-striatum, which will help us understand the mechanism behind neurodegeneration postulated above and provide insights into developing disease-modifying therapeutics. It was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During L-DOPA therapy, it was observed that higher L-DOPA dosage results in increased loss of terminals in SNc. It was also observed that co-administration of L-DOPA and glutathione (antioxidant) evades L-DOPA-induced toxicity in SNc neurons. Our proposed model of the SNc-striatum system is the first of its kind, where SNc neurons were modeled at a biophysical level, and striatal neurons were modeled at a spiking level. We show that our proposed model was able to capture L-DOPA-induced toxicity in SNc, caused by energy deficiency.
The landscape of therapeutics for mild cognitive impairment and dementia is quite limited. While many single-agent trials of pharmaceuticals have been conducted, these trials have repeatedly been unable to show improvement in cognition. It is hypothesized that because Alzheimer’s, like many other chronic illnesses, is not a monogenic illness, but is instead caused by the downstream effects of an individual’s genetic variants interacting with each other, the environment, and lifestyle, that improving outcomes will require a personalized, precision medicine approach. This approach requires identifying and then addressing contributing genomic and other factors specific to each individual in a simultaneous fashion. Until recently, the utility of genomics as part of clinical decision-making for Alzheimer’s and cognitive decline has been limited by the lack of availability of a genomic platform designed specifically to evaluate factors contributing to cognitive decline and how to respond to these factors The clinical decision support (CDS) platform used in the cases presented focuses on common variants that relate to topics including, but not limited to brain inflammation, amyloid processing, nutrient carriers, brain ischemia, oxidative stress, and detoxification pathways. Potential interventions based on the scientific literature were included in the CDS, but the final decision on what interventions to apply were chosen by each patient’s physician. Interventions included supplements with “generally regarded as safe (GRAS)” rating, along with targeted diet and lifestyle modifications. We hypothesize that a personalized genomically targeted approach can improve outcomes for individuals with mild cognitive impairment who are at high risk of Alzheimer’s. The cases presented in this report represent a subset of cases from three physicians’ offices and are meant to provide initial proof of concept data demonstrating the efficacy of this method and provide support for this hypothesis. These patients were at elevated risk for Alzheimer’s due to their apolipoprotein E ε4 status. While further prospective and controlled trials need to be done, initial case reports are encouraging and lend support to this hypothesis of the benefit of a genomically targeted personalized medicine approach to improve outcomes in individuals with cognitive decline who are at high risk for Alzheimer’s.
Astrocytes are the major glial constituents of the central nervous system and are critical for brain function. Despite this, it is relatively recently that researchers have started considering these niche cells for possible involvement in neurodegenerative diseases such as Parkinson’s disease (PD). PD is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). While neuronal Lewy Body inclusions in dopaminergic neurons comprising mainly of α-synuclein serves as a pathological hallmark of PD, recent studies have shown α-synuclein immunoreactive inclusions even in astrocytes of PD patient brains. Several studies have also reported that genes known to have a causative role in the development of PD are expressed in astrocytes and have important roles in astrocyte function. Astrocytes are multifunctional cells contributing to the survival and maintenance of neuronal health, ion buffering, neurotransmitter recycling, and regulation of the blood-brain barrier. Consequences of the loss of normal homeostatic functions and an increase in toxic functions in astrocytes are thus probably involved in the onset and progression of PD. Further, the complex role of astrocytes is influenced by region-specificity and the number of astrocytes for the survival of dopaminergic neurons. Indeed, studies have demonstrated regional variability in gene expression of astrocytes of the cortex, cerebellum, brainstem, and hypothalamus. These emerging roles of astrocytes in the pathogenesis of PD constitute an exciting development with promising novel therapeutic targets to modify the hostile microenvironment of substantia nigra during PD. Understanding these niche cells is also of prime importance for designing approaches for prophylactic and regenerative strategies through derivation of exogenous niche cells from patient-specific iPSCs or mesenchymal stromal cells. Here, we review the potential protective and deleterious effects of astrocytes in the substantia nigra of PD and explore how recent developments can in turn impact our understanding of the pathophysiology of PD and its treatment.
Background
Growing evidence suggests an association between Parkinson’s disease (PD) and diabetes mellitus (DM). At the cellular level, long-term elevated levels of glucose have been shown to lead to nigrostriatal degeneration in PD models. However, the underlying mechanism is still unclear. Previously, we have elucidated the potential of type 2 diabetes mellitus (T2DM) in facilitating PD progression, involving aggregation of both alpha-synuclein (α-syn) and islet amyloid polypeptide in the pancreatic and brain tissues. However, due to the complicated effect of insulin resistance on PD onset, the actual mechanism of hyperglycemia-induced dopaminergic degeneration remains unknown.
Methods
We employed the type 1 diabetes mellitus (T1DM) model induced by streptozotocin (STZ) injection in a transgenic mouse line (BAC-α-syn-GFP) overexpressing human α-syn, to investigate the direct effect of elevated blood glucose on nigrostriatal degeneration.
Results
STZ treatment induced more severe pathological alterations in the pancreatic islets and T1DM symptoms in α-syn-overexpressing mice than in wild-type mice, at one month and three months after STZ injections. Behavioral tests evaluating motor performance confirmed the nigrostriatal degeneration. Furthermore, there was a marked decrease in dopaminergic profiles and an increase of α-syn accumulation and Serine 129 (S129) phosphorylation in STZ-treated α-syn mice compared with the vehicle-treated mice. In addition, more severe neuroinflammation was observed in the brains of the STZ-treated α-syn mice.
Conclusion
Our results solidify the potential link between DM and PD, providing insights into how hyperglycemia induces nigrostriatal degeneration and contributes to pathogenic mechanisms in PD.
Parkinson’s disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.
Glutathione is an important antioxidant that plays a crucial role in the cellular protection against oxidative stress and detoxification of electrophilic mutagens, and carcinogens. Glutathione transferases are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of toxic compounds, processes followed by subsequent excretion of the detoxified products. Degeneration and loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal neurons generally involves oxidative stress, neuroinflammation, alpha-synuclein aggregation to neurotoxic oligomers, mitochondrial dysfunction, protein degradation dysfunction, and endoplasmic reticulum stress. However, it is still unclear what triggers these neurodegenerative processes. It has been reported that aminochrome may elicit all of these mechanisms and, interestingly, aminochrome is formed inside neuromelanin-containing dopaminergic neurons during neuromelanin synthesis. Aminochrome is a neurotoxic ortho-quinone formed in neuromelanin synthesis. However, it seems paradoxical that the neurotoxin aminochrome is generated during neuromelanin synthesis, even though healthy seniors have these neurons intact when they die. The explanation of this paradox is the existence of protective tools against aminochrome neurotoxicity composed of the enzymes DT-diaphorase, expressed in these neurons, and glutathione transferase M2-2, expressed in astrocytes. Recently, it has been reported that dopaminergic neurons can be protected by glutathione transferase M2-2 from astrocytes, which secrete exosomes containing the protective enzyme.
Parkinson disease (PD) used to be considered a nongenetic condition. However, the identification of several autosomal dominant and recessive mutations linked to monogenic PD has changed this view. Clinically manifest PD is then thought to occur through a complex interplay between genetic mutations, many of which have incomplete penetrance, and environmental factors, both neuroprotective and increasing susceptibility, which variably interact to reach a threshold over which PD becomes clinically manifested. Functional studies of PD gene products have identified many cellular and molecular pathways, providing crucial insights into the nature and causes of PD. PD originates from multiple causes and a range of pathogenic processes at play, ultimately culminating in nigral dopaminergic loss and motor dysfunction. An in-depth understanding of these complex and possibly convergent pathways will pave the way for therapeutic approaches to alleviate the disease symptoms and neuroprotective strategies to prevent disease manifestations. This review is aimed at providing a comprehensive understanding of advances made in PD research based on leveraging genetic insights into the pathogenesis of PD. It further discusses novel perspectives to facilitate identification of critical molecular pathways that are central to neurodegeneration that hold the potential to develop neuroprotective and/or neurorestorative therapeutic strategies for PD. SIGNIFICANCE STATEMENT: A comprehensive review of PD pathophysiology is provided on the complex interplay of genetic and environmental factors and biologic processes that contribute to PD pathogenesis. This knowledge identifies new targets that could be leveraged into disease-modifying therapies to prevent or slow neurodegeneration in PD.
Recently, it has been reported that dysfunction of astrocytes is involved vulnerability of neuronal cells in several neurological disorders. Glutathione (GSH) is the most abundant intrinsic antioxidant in the central nervous system, and its substrate cysteine is readily becomes the oxidized dimeric cystine. Since neurons lack a cystine transport system, neuronal GSH synthesis depends on cystine uptake via the cystine/glutamate exchange transporter (xCT), GSH synthesis and release in/from surrounding astrocytes. The expression and release of the zinc-binding protein metallothionein (MT) in astrocytes, which is a strong antioxidant, is induced and exerts neuroprotective in the case of dopaminergic neuronal damage. In addition, the transcription factor Nrf2 induces expression of MT-1 and GSH related molecules. We previously revealed that several antiepileptic drugs, serotonin 5-HT1A receptor agonists, plant-derived chemicals (phytochemicals) increased xCT expression, Nrf2 activation, GSH or MT expression and release in/from astrocytes, and exerted a neuroprotective effect against dopaminergic neurodegeneration in Parkinson’s disease model. Our serial studies on neuroprotection via antioxidant defense mechanism of astrocytes have found three target molecular systems of astrocytes for neuroprotection: (1) xCT-GSH synthetic system, (2) Nrf2 system and (3) 5-HT1A receptor-Nrf2-MT system, 5-HT1A-S100β system. In this article, possible neuroprotective strategy for Parkinson’s disease has been reviewed targeting antioxidative molecules in astrocytes.
Parkinson’s disease (PD) is increasingly thought to be associated with glial pathology. Recently, research in neurodegenerative disorders has applied a greater focus to better understanding the role of astrocytes in the disease pathophysiology. In this article, we review results from the latest preclinical and clinical work, including functional imaging studies on astrocytes in PD and highlight key molecules that may prove valuable as biomarkers. We discuss how astrocytes may contribute to the initiation and progression of PD. We additionally present trials of investigational medicinal products and the current background for the design of future clinical trials.
Cambridge Core - Neurology and Clinical Neuroscience - Brain Fables - by Alberto Espay
This paper presents an evidence-based strategy for improving clinical outcomes in COVID-19. Recommendations are based on the phases of the disease, because optimal interventions for one phase may not be appropriate for a different phase. The four phases addressed are: Prevention, Infection, Inflammation and Recovery. Underlying this phased approach is recognition of emerging evidence for two different components of pathophysiology, early infection and late stage severe complications. These two aspects of the disease suggest two different patterns of clinical emphasis that seem on the surface to be not entirely concordant. We describe the application of therapeutic strategies and appropriate tactics that address four main stages of disease progression for COVID-19. Emerging evidence in COVID-19 suggests that the SARS-CoV-2 virus may both evade the innate immune response and kill macrophages. Delayed innate immune response and a depleted population of macrophages can theoretically result in a blunted antigen presentation, delaying and diminishing activation of the adaptive immune response. Thus, one clinical strategy involves supporting patient innate and adaptive immune responses early in the time course of illness, with the goal of improving the timeliness, readiness, and robustness of both the innate and adaptive immune responses. At the other end of the disease pathology spectrum, risk of fatality in COVID-19 is driven by excessive and persistent upregulation of inflammatory mechanisms associated with cytokine storm. Thus, the second clinical strategy is to prevent or mitigate excessive inflammatory response to prevent the cytokine storm associated with high mortality risk. Clinical support for immune system pathogen clearance mechanisms involves obligate activation of immune response components that are inherently inflammatory. This puts the goals of the first clinical strategy (immune activation) potentially at odds with the goals of the second strategy(mitigation of proinflammatory effects). This creates a need for discernment about the time course of the illness and with that, understanding of which components of an overall strategy to apply at each phase of the time course of the illness. We review evidence from early observational studies and the existing literature on both outcomes and mechanisms of disease, to inform a phased approach to support the patient at risk for infection, with infection, with escalating inflammation during infection, and at risk of negative sequelae as they move into recovery.
Somnolence is a recognized adverse effect of dopamine agonists. Two new dopamine agonists, pramipexole and ropinirole, have been reported to cause sudden-onset sleep spells in patients with Parkinson disease (PD) while they were driving. The frequency of these spells and whether driving should be restricted has yet to be established.
To determine the frequency of and predictors for sudden-onset sleep and, particularly, episodes of falling asleep while driving among patients with PD.
Prospective survey conducted between January and April 2000 in 18 clinics directed by members of the Canadian Movement Disorders Group; 638 consecutive highly functional PD patients without dementia were enrolled, of whom 420 were currently drivers.
Excessive daytime sleepiness and sudden-onset sleep as assessed by the Epworth Sleepiness Scale and the Inappropriate Sleep Composite Score. The latter score, designed for this study, addressed falling asleep in unusual circumstances. The 2 scales were combined in 3 separate formats: dozing off, sudden unexpected sleep, and sudden blank spells.
Excessive daytime sleepiness was present overall in 327 (51%) of the 638 patients and in 213 (51%) of the 420 drivers. Patients taking a variety of different dopamine agonists had no differences in Epworth sleepiness scores, in the composite score, or in the risk of falling asleep while driving. Sixteen patients (3.8%) had experienced at least 1 episode of sudden onset of sleep while driving (after the diagnosis of PD); in 3 (0.7%), it occurred without warning. The 2 risk factors associated with falling asleep at the wheel were the Epworth Sleepiness Scale score (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.24) and the Inappropriate Sleep Composite Score (OR, 2.54; 95% CI, 1.76-3.66). A standard Epworth Sleepiness Scale score of 7 or higher predicted 75% of episodes of sleep behind the wheel at a specificity of 50% (exclusion of the question related to driving provided 70% sensitivity and 52% specificity), whereas a score of 1 on the Inappropriate Sleep Composite Score generated a sensitivity of 52% and specificity of 82%.
Excessive daytime sleepiness is common even in patients with PD who are independent and do not have dementia. Sudden-onset sleep without warning is infrequent. The Epworth score has adequate sensitivity for predicting prior episodes of falling asleep while driving and its specificity can be increased by use of the Inappropriate Sleep Composite Score. It is unknown if routinely performing these assessments could be more effective in predicting future risk for these rare sleep attacks. Patients should be warned not to drive if they doze in unusual circumstances.
We performed experiments to determine whether nitric oxide promoted the formation of intracellular S-nitrosothiol adducts in human neutrophils. At concentrations sufficient to inhibit chemoattractant-induced superoxide anion production, nitric oxide caused a depletion of measurable intracellular glutathione as determined by both the monobromobimane HPLC method and the glutathione reductase recycling assay. The depletion of glutathione could be shown to be due to the formation of intracellular S-nitrosoglutathione as indicated by the ability of sodium borohydride treatment of cytosol to result in the complete recovery of measurable glutathione. The formation of intracellular S-nitrosylated compounds was confirmed by the capacity of cytosol derived from nitric oxide-treated cells to ADP-ribosylate glyceraldehyde-3-phosphate dehydrogenase. Depletion of intracellular glutathione was accompanied by a rapid and concomitant activation of the hexose monophosphate shunt (HMPS) following exposure to nitric oxide. Kinetic studies demonstrated that nitric oxide-dependent activation of the HMPS was reversible and paralleled nitric oxide-induced glutathione depletion. Synthetic preparations of S-nitrosoglutathione shared with nitric oxide the capacity to inhibit superoxide anion production and activate the HMPS. These data suggest that nitric oxide may regulate cellular functions via the formation of intracellular S-nitrosothiol adducts and the activation of the HMPS.
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. 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. 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. Our data indicate that in untreated PD patients GSH has symptomatic efficacy and possibly retards the progression of the disease.
Glutathione is a storage form of cysteine and protects against reactive oxygen species and potentially toxic xenobiotics in the central nervous system. Marked reductions in intracellular or intramitochondrial glutathione are associated with cell death. Enzymes involved in glutathione metabolism are very active in the choroid plexus, and astrocytes maintain a high concentration of glutathione. Astrocytes probably play an important role in regulating cerebral sulfur/glutathione metabolism and in protecting the brain against noxious chemicals. Oxidative stress contributes to age-related neurodegenerative diseases. Patients with inborn errors of glutathione metabolism often exhibit progressive neurological problems. Therefore, increasing brain glutathione levels may have therapeutic benefits.
Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.
Parkinson's disease is a neurodegenerative disorder characterized by the preferential loss of midbrain dopaminergic neurons in the substantia nigra (SN). One of the earliest detectable biochemical alterations that occurs in the Parkinsonian brain is a marked reduction in SN levels of total glutathione (glutathione plus glutathione disulfide), occurring before losses in mitochondrial complex I (CI) activity, striatal dopamine levels, or midbrain dopaminergic neurodegeneration associated with the disease. Previous in vitro data from our laboratory has suggested that prolonged depletion of dopaminergic glutathione results in selective impairment of mitochondrial complex I activity through a reversible thiol oxidation event. To address the effects of depletion in dopaminergic glutathione levels in vivo on the nigrostriatal system, we created genetically engineered transgenic mouse lines in which expression of gamma-glutamyl cysteine ligase, the rate-limiting enzyme in de novo glutathione synthesis, can be inducibly downregulated in catecholaminergic neurons, including those of the SN. A novel method for isolation of purified dopaminergic striatal synaptosomes was used to study the impact of dopaminergic glutathione depletion on mitochondrial events demonstrated previously to occur in vitro as a consequence of this alteration. Dopaminergic glutathione depletion was found to result in a selective reversible thiol-oxidation-dependent mitochondrial complex I inhibition, followed by an age-related nigrostriatal neurodegeneration. This suggests that depletion in glutathione within dopaminergic SN neurons has a direct impact on mitochondrial complex I activity via increased nitric oxide-related thiol oxidation and age-related dopaminergic SN cell loss.
This chapter discusses the reaction of superoxide with glutathione (GSH) and other thiols. To detect a reaction with superoxide, it is necessary to add GSH or the thiol of interest to a superoxide-generating system and measure either thiol oxidation or oxygen consumption. The involvement of superoxide is verified by inhibiting the reaction with superoxide dismutase. Because superoxide is regenerated, competition assays do not detect the reaction and are inappropriate. The source of superoxide can be either radiolytic or enzymatic. Because it is not possible to generate superoxide without producing other radicals (for example, OH·) or hydrogen peroxide either directly or by dismutation, these must be taken into account when interpreting the results. The existence of a reaction between the thiol and superoxide can be established using superoxide dismutase, but the complexity of the reaction sequence makes analysis difficult. The xanthine oxidase system produces superoxide as the only initial radical, but it also produces hydrogen peroxide. This is not a radical reaction and can be separated from the superoxide-dependent chain. It involves the thiolate anion, and its rate increases with increasing pH. Whether hydrogen peroxide is produced or not can be determined by measuring oxygen uptake in the presence and absence of catalase, but it is more accurate to measure peroxide production directly. This is best accomplished using a hydrogen peroxide electrode.
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 (40% compared to control subjects) and GSSG levels were marginally (29%) but insignificantly elevated; there were no changes in other brain areas. The only significant change in multiple-system atrophy was an increase of GSH (196%) coupled with a reduction of GSSG (60%) in the globus pallidus. The only change in progressive supranuclear palsy was a reduced level of GSH in the caudate nucleus (51%). The only change in Huntington's disease was a reduction of GSSG in the caudate nucleus (50%). Despite profound nigral cell loss in the substantia nigra in Parkinson's disease, multiple-system atrophy, and progressive supranuclear palsy, 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.
Glutathione transferase activity and total glutathione (GSH) content were measured in several regions of autopsied brain from patients dying with idiopathic Parkinson's disease (PD) or progressive supranuclear palsy (PSP), and from control subjects. 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.
Reduced and oxidized glutathione concentrations in post-mortem brain tissue from the substantia nigra of control subjects and patients with neuropathologically confirmed Parkinson's disease were measured by a coulometric method using high-pressure liquid chromatography and electrochemical detection. Reduced glutathione concentrations were decreased in the substantia nigra of parkinsonian patients compared with controls. Differences in the concentration of oxidized glutathione and in the percentage of oxidized glutathione of the total glutathione were not observed between parkinsonian and control subjects. The finding that oxidized glutathione is not decreased in Parkinson's disease suggests that the decrease in reduced glutathione is not exclusively the consequence of neuronal loss in the substantia nigra but may indicate a state of oxidative stress.
The regional distributions of iron, copper, zinc, magnesium, and calcium in parkinsonian brains were compared with those of matched controls. In mild Parkinson's disease (PD), there were no significant differences in the content of total iron between the two groups, whereas there was a significant increase in total iron and iron (III) in substantia nigra of severely affected patients. Although marked regional distributions of iron, magnesium, and calcium were present, there were no changes in magnesium, calcium, and copper in various brain areas of PD. The most notable finding was a shift in the iron (II)/iron (III) ratio in favor of iron (III) in substantia nigra and a significant increase in the iron (III)-binding, protein, ferritin. A significantly lower glutathione content was present in pooled samples of putamen, globus pallidus, substantia nigra, nucleus basalis of Meynert, amygdaloid nucleus, and frontal cortex of PD brains with severe damage to substantia nigra, whereas no significant changes were observed in clinicopathologically mild forms of PD. In all these regions, except the amygdaloid nucleus, ascorbic acid was not decreased. Reduced glutathione and the shift of the iron (II)/iron (III) ratio in favor of iron (III) suggest that these changes might contribute to pathophysiological processes underlying PD.
The activities of enzymes related to glutathione synthesis, degradation, and function were analyzed in various brain regions (cerebral cortex, caudate nucleus, putamen, globus pallidus, and substantia nigra) from patients dying with pathologically proven Parkinson's disease (PD) and multiple system atrophy (MSA), and from matched controls with no neurological disorder. The activity of the glutathione degradative enzyme, gamma-glutamyltranspeptidase, was selectively elevated in substantia nigra (SN) in PD. In contrast, the activity of the synthetic enzyme, gamma-glutamylcysteine synthetase, was unaltered in SN and other brain areas in PD. Similarly, glutathione peroxidase and glutathione transferase activities were unaltered in SN or in other brain regions in PD. gamma-Glutamylcysteine synthetase, gamma-glutamyltranspeptidase, glutathione peroxidase, and glutathione transferase activities were normal in SN and most other brain areas in MSA. However, glutathione peroxidase activity was increased in the lateral globus pallidus and caudate nucleus in MSA. The depletion of reduced glutathione (GSH) in the SN in PD, with no change in oxidized glutathione (GSSG), may be due to efflux of GSH mainly out of glia promoted by gamma-glutamyltranspeptidase, perhaps with additional increased conversion of GSH to GSSG (which itself is transported out of cells by gamma-glutamyltranspeptidase), in response to increased hydrogen peroxide formation.
Using a vascular brain perfusion model in the guinea-pig, the net uptake of [35S]-GSH by the brain was found to be linear and similar in various regions during 10 min perfusion. Dual labeled [35S and 3H] GSH taken up by the brain had the same isotope ratio as the injected stock whether or not gamma- glutamyl transferase was inhibited. Greater than 96% of brain uptake of [35S]-cysteine-labeled GSH and [3H]-glycine-labeled GSH were in intact form. Transcytosis of [35S]-GSH from lumen into brain parenchyma was demonstrated using a capillary depletion technique. Both GSH and GSH-monoethyl ester inhibited [35S]-GSH transport. Thus, we have demonstrated blood-brain barrier extraction of circulating GSH in a brain perfusion model, and the transcytosis of intact GSH into the brain parenchyma without breakdown.
Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age-matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects. Similarly, ferritin levels in the substantia nigra and other brain areas were unaltered. There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects. Rotenone-sensitive NADH coenzyme Q1 reductase activity (complex I) was reduced to levels intermediate between those in control subjects and those in patients with overt Parkinson's disease, but this change did not reach statistical significance. The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects. Reduced glutathione levels in other brain regions were unaffected and there were no changes in oxidized glutathione levels in any brain region. Altered iron metabolism is not detectable in the early stages of nigral dopamine cell degeneration. There may be some impairment of mitochondrial complex I activity in the substantia nigra in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Hyperoxidation phenomena are suspected to be involved in dopaminergic cell death in Parkinson's disease, which affects preferentially the neuromelanin-containing dopaminergic neurons of the substantia nigra. Glutathione peroxidase is the major protective enzyme against hydrogen peroxide toxicity. The distribution of glutathione peroxidase-containing cells was investigated by immunohistochemistry in the midbrain of four control subjects and four patients with Parkinson's disease. (1) Glutathione peroxidase-like immunoreactivity was detected exclusively in glial cells. (2) In control brains, the density of glutathione peroxidase-positive cells was higher in the vicinity of the dopaminergic cell groups known to be resistant to the pathological process of Parkinson's disease. (3) In Parkinson's disease, an increased density of glutathione peroxidase-immunostained cells was observed, surrounding the surviving dopaminergic neurons. The increase in glutathione peroxidase-containing cells was correlated with the severity in dopaminergic cell loss in the respective cell groups. The data suggest that in control brains, a low density of glutathione peroxidase-positive cells surround the dopaminergic neurons the most vulnerable to Parkinson's disease, and that in parkinsonian brains, the increased number of glutathione peroxidase-positive cells may contribute to protect neurons against pathological death. Thus, the amount of glutathione peroxidase protein-containing cells may be critical for a protective effect against oxidative stress, although it cannot be excluded that the level of the enzyme activity remains the crucial factor.
The role of oxidative stress in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity is as yet unclear and the evidence for generation of oxygen free radicals as a primary event in the neurotoxicity is yet to be demonstrated. The present study was undertaken to ascertain the potential role of oxidative damage, and the protective role, if any, of the antioxidant, glutathione (GSH), in MPTP-induced neurotoxicity. Exposure of sagittal slices of mouse brain to MPTP resulted in significant increases of reactive oxygen species (ROS) and malondialdehyde (MDA, the product of lipid peroxidation) and decreases in GSH content. Pretreatment of mouse brain slices, in vitro, with GSH or GSH isopropyl ester attenuated MPTP toxicity as assessed by the tissue activity of the mitochondrial enzyme, NADH-dehydrogenase (NADH-DH), and by leakage of the cytosolic enzyme, lactate dehydrogenase (LDH), from the slice into the medium. In vivo administration of MPTP (30 mg/kg body weight, s.c.), to mice resulted in significant lowering of GSH in the striatum and midbrain, 2 h after dosage; ROS levels in the striatum and midbrain increased after 4 and 8 h, respectively. In the striatum significant inhibition of rotenone-sensitive NADH ubiquinone-1 oxido-reductase (Complex 1) was observed transiently 1 h after MPTP administration. The enzyme activity recovered thereafter; significant inhibition of mitochondrial Complex I was observed in the striatum only 18 h after MPTP dose. In the midbrain, mitochondrial Complex I was inhibited only 18 h after MPTP dose; no change was observed at the early time points examined. Thus, the depletion of GSH and increased ROS formation preceded the inhibition of the mitochondrial enzyme in the midbrain. Evidence presented herein from both in vitro and in vivo studies support that MPTP exposure generates ROS resulting in oxidative stress.
We have previously shown GSH transport across the blood-brain barrier in vivo and expression of transport in Xenopus laevis oocytes injected with bovine brain capillary mRNA. In the present study, we have used MBEC-4, an immortalized mouse brain endothelial cell line, to establish the presence of Na +-dependent and Na +-independent GSH transport and have localized the Na +-dependent transporter using domain-enriched plasma membrane vesicles. In cells depleted of GSH with buthionine sulfoximine, a significant increase of intracellular GSH could be demonstrated only in the presence of Na +. Partial but significant Na + dependency of [ 35S]GSH uptake was observed for two GSH concentrations in MBEC-4 cells in which γ-glutamyltranspeptidase and γ- glutamylcysteine synthetase were inhibited to ensure absence of breakdown and resynthesis of GSH. Uniqueness of Na +-dependent uptake in MBEC-4 cells was confirmed with parallel uptake studies with Cos-7 cells that did not show this activity. Molecular form of uptake was verified as predominantly GSH, and very little conversion of [ 35S]cysteine to GSH occurred under the same incubation conditions. Poly(A) + RNA from MBEC expressed GSH uptake with significant (~40-70%) Na + dependency, whereas uptake expressed by poly(A) + RNA from HepG2 and Cos-1 cells was Na + independent. Plasma membrane vesicles from MBEC were separated into three fractions (30, 34, and 38% sucrose, by wt) by density gradient centrifugation. Na +-dependent glucose transport, reported to be localized to the abluminal membrane, was found to be associated with the 38% fraction (abluminal). Na +-dependent GSH transport was present in the 30% fraction, which was identified as the apical (luminal) membrane by localization of P-glycoprotein 170 by western blot analysis. Localization of Na +-dependent GSH transport to the luminal membrane and its ability to drive up intracellular GSH may find application in the delivery of supplemented GSH to the brain in vivo.
The tripeptide glutathione (GSH) has been thoroughly investigated in relation to its role as antioxidant and free radical scavenger. In recent years, novel actions of GSH in the nervous system have also been described, suggesting that GSH may serve additionally both as a neuromodulator and as a neurotransmitter. In the present article, we describe our studies to explore further a potential role of GSH as neuromodulator/neurotransmitter. These studies have used a combination of methods, including radioligand binding, synaptic release and uptake assays, and electrophysiological recording. We report here the characteristics of GSH binding sites, the interrelationship of GSH with the NMDA receptor, and the effects of GSH on neural activity. Our results demonstrate that GSH binds via its gamma-glutamyl moiety to ionotropic glutamate receptors. At micromolar concentrations GSH displaces excitatory agonists, acting to halt their physiological actions on target neurons. At millimolar concentrations, GSH, acting through its free cysteinyl thiol group, modulates the redox site of NMDA receptors. As such modulation has been shown to increase NMDA receptor channel currents, this action may play a significant role in normal and abnormal synaptic activity. In addition, GSH in the nanomolar to micromolar range binds to at least two populations of binding sites that appear to be distinct from all known excitatory amino acid receptor subtypes. GSH bound to these sites is not displaceable by glutamatergic agonists or antagonists. These binding sites, which we believe to be distinct receptor populations, appear to recognize the cysteinyl moiety of the GSH molecule. Like NMDA receptors, the GSH binding sites possess a coagonist site(s) for allosteric modulation. Furthermore, they appear to be linked to sodium ionophores, an interpretation supported by field potential recordings in rat cerebral cortex that reveal a dose-dependent depolarization to applied GSH that is blocked by the absence of sodium but not by lowering calcium or by NMDA or (S)-2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate antagonists. The present data support a reevaluation of the role of GSH in the nervous system in which GSH may be involved both directly and indirectly in synaptic transmission. A full accounting of the actions of GSH may lead to more comprehensive understanding of synaptic function in normal and disease states.
The purpose of the present study was to identify and localize glutathione (GSH) transport in an in vitro tissue culture model of blood-brain barrier (BBB). The localization of Na+-dependent GSH transport in an immortalized cell line of human cerebrovascular endothelial cells (HCEC) and asymmetry of transport in Transwell studies were investigated. Initial studies with cultured HCEC established a significant (45%) Na+-dependency for GSH uptake in cultured HCEC pretreated with acivicin, an inhibitor of gamma-glutamyltranspeptidase (GGT). Transendothelial electrical resistance (TEER) and uptake of [35S]GSH from luminal and abluminal fluids of HCEC were measured in Na+-containing and Na+-free (choline chloride) buffers using cells grown on gelatin-coated membrane filters. TEER of HCEC monolayers in regular medium was 40.1 +/- 8.0 ohms cm2. Human astrocyte-conditioned medium (ACM) caused no change in TEER, but increased GGT activity approximately threefold when measured in cell lysates. Luminal and abluminal GSH uptake increased in a time-dependent fashion and were not affected by inhibition of GGT activity with acivicin. Sodium dependency was only observed for luminal uptake (Na+-containing 2.41 +/- 0.15 vs. Na+-free 0.96 +/- 0.03 pmol/30 min/million cells, p < 0.001) but not for abluminal uptake (1.02 +/- 0.13 vs. 1.11 +/- 09, p > 0.05). Apparent efflux via the luminal membrane was lower in the presence of sodium as compared to that without sodium, further suggesting that a Na+-dependent uptake process for GSH is operative at this membrane. GSH uptake and efflux were also demonstrated in neonatal rat and fetal human astrocytes, both exhibiting partial Na+-dependency of uptake. In conclusion, our results show for the first time, that HCEC and astrocytes take up GSH by both Na+-dependent and -independent mechanisms. The Na+-dependent GSH transport process in HCEC appears to be localized to luminal plasma membranes of HCEC.
A decrease in total glutathione, and aberrant mitochondrial bioenergetics have been implicated in the pathogenesis of Parkinson's disease. Our previous work exemplified the importance of glutathione (GSH) in the protection of mesencephalic neurons exposed to malonate, a reversible inhibitor of mitochondrial succinate dehydrogenase/complex II. Additionally, reactive oxygen species (ROS) generation was an early, contributing event in malonate toxicity. Protection by ascorbate was found to correlate with a stimulated increase in protein-glutathione mixed disulfide (Pr-SSG) levels. The present study further examined ascorbate-glutathione interactions during mitochondrial impairment. Depletion of GSH in mesencephalic cells with buthionine sulfoximine potentiated both the malonate-induced toxicity and generation of ROS as monitored by dichlorofluorescein diacetate (DCF) fluorescence. Ascorbate completely ameliorated the increase in DCF fluorescence and toxicity in normal and GSH-depleted cultures, suggesting that protection by ascorbate was due in part to upstream removal of free radicals. Ascorbate stimulated Pr-SSG formation during mitochondrial impairment in normal and GSH-depleted cultures to a similar extent when expressed as a proportion of total GSH incorporated into mixed disulfides. Malonate increased the efflux of GSH and GSSG over time in cultures treated for 4, 6 or 8 h. The addition of ascorbate to malonate-treated cells prevented the efflux of GSH, attenuated the efflux of GSSG and regulated the intracellular GSSG/GSH ratio. Maintenance of GSSG/GSH with ascorbate plus malonate was accompanied by a stimulation of Pr-SSG formation. These findings indicate that ascorbate contributes to the maintenance of GSSG/GSH status during oxidative stress through scavenging of radical species, attenuation of GSH efflux and redistribution of GSSG to the formation of mixed disulfides. It is speculated that these events are linked by glutaredoxin, an enzyme shown to contain both dehydroascorbate reductase as well as glutathione thioltransferase activities.
The pathogenesis underlying the selective degeneration of nigral dopaminergic neurons in Parkinson's disease is not fully understood but several lines of evidence implicate the role of oxidative stress and mitochondrial dysfunction. Depletion in levels of the thiol reducing agent glutathione (GSH + GSSG) is the earliest reported biochemical event to occur in the Parkinsonian substantia nigra prior to selective loss of complex I (CI) activity associated with the disease believed to contribute to subsequent dopaminergic cell death. Recent studies from our laboratory have demonstrated that acute reduction in both cellular and mitochondrial glutathione levels results in increased oxidative stress and a decrease in mitochondrial function linked to a selective decrease in CI activity through an NO-mediated mechanism (Jha, N.; Jurma, O.; Lalli, G.; Liu, Y.; Pettus, E. H.; Greenamyre, J. T.; Liu, R. M.; Forman, H. J.; Andersen, J. K. Glutathione depletion in PC12 results in selective inhibition of mitochondrial complex I activity. Implications for Parkinson's disease J. Biol. Chem. 275: 26096-26101; 2000. Hsu, M.; Srinivas, B.; Kumar, J.; Subramanian, R.; Andersen, J. Glutathione depletion resulting in selective mitochondrial complex I inhibition in dopaminergic cells is via an NO-mediated pathway not involving peroxynitrite: implications for Parkinson's disease J. Neurochem. 92: 1091-1103.2005.). However, the effect of prolonged glutathione depletion on dopaminergic cells is not known. In this present study, using low concentrations of buthionine-S-sulfoximine, a chemical inhibitor of the de novo glutathione synthesizing enzyme glutamate cysteine ligase, we developed a chronic model in which glutathione depletion in dopaminergic N27 cells for a 7-day period was found to lead to inhibition of CI activity via a peroxynitrite-mediated event which is reversible by the thiol reducing agent, dithiothreitol, and coincides with increased S-nitrosation of mitochondrial proteins.