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Modified Columbia University Rating Scale: Total Scores in 9 Patients with Parkinson's Disease Treated with GSH (600 mg/day, I.V.) or Levodopa (375 mg/day + DCI, per OS).
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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 t...
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... total scores for parkinsonian disability (modified CURS) were significantly lower either after GSH therapy, with respect to baseline (p < 0.007 ), or after levodopacarbidopa with respect to the wash-out period (p c 0.01). (Table 2). A significant improvement after GSH therapy, with respect to baseline, of modified CURS subscores, was evidenced for speech, hypomimia, rigidity, pronation and supination of hands, foot taping, posture, gait, balance and hypokinesia (from p < 0.02, to p c 0.007). ...Citations
... GSH is the most abundant nonprotein peptide in the body and is responsible for maintaining cellular redox status. The application of GSH as a therapeutic agent is limited by its very short half-life in human plasma and its difficulty in crossing cell membranes [116]. Under physiological conditions, the cellular availability of cysteine is considered to be the rate-limiting factor in the synthesis of intracellular GSH [117]. ...
There are currently no disease-modifying therapies for Parkinson’s disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients’ brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.
... 49 In patients with acute hepatitis due to alcohol use or hepatitis infection, administration of glutathione injection (600 mg) for 7 days was tolerated well and significantly improved liver enzymes. 34 In small-scale study involving 9 patients with Parkinson's disease who received intravenous GSH (600 mg, twice daily) and assessed over a period of 30 days, 53 showed improvement in clinical outcomes with a 42% decline in clinical disability caused by Parkinson's disease. 53 The therapeutic effect of GSH reportedly lasted for 2-4 months. ...
... 34 In small-scale study involving 9 patients with Parkinson's disease who received intravenous GSH (600 mg, twice daily) and assessed over a period of 30 days, 53 showed improvement in clinical outcomes with a 42% decline in clinical disability caused by Parkinson's disease. 53 The therapeutic effect of GSH reportedly lasted for 2-4 months. 53 In 2009, Milla et al. assessed the use of intravenous GSH (1500 mg/mL) in managing neurotoxicity caused by oxaliplatin infusion in 27 colorectal cancer patients. ...
... 53 The therapeutic effect of GSH reportedly lasted for 2-4 months. 53 In 2009, Milla et al. assessed the use of intravenous GSH (1500 mg/mL) in managing neurotoxicity caused by oxaliplatin infusion in 27 colorectal cancer patients. 51 They observed a significant decrease in neurotoxicity compared to the placebo group, without any adverse events. ...
Alcoholic liver disease (ALD) and sepsis are life-threatening conditions marked by severe oxidative stress. Chronic alcohol use triggers oxidative stress and inflammation that damages liver cells. Glutathione (GSH), a tripeptide consisting of gamma glutamyl cysteinyl glycine possesses a thiol group and participates in oxidation reduction reactions, acting as a principal cellular scavenger of free radicles. GSH is present in large concentrations in the liver, and its endogenous levels are depleted in ALD, exacerbating the condition. Intravenous GSH supplementation has shown promising results in improving liver function and reducing fibrosis markers in ALD patients. Intravenous GSH treatment has demonstrated the potential to reduce oxidative injury and mortality rates in patients with sepsis in the intensive care unit. The versatility of GSH in mitigating oxidative stress, inflammation, and tissue damage and proven safety and tolerability profile make it a valuable adjunct to current treatments. Further research is imperative to comprehensively unravel the therapeutic benefits of GSH injection adjunct to standard of care in patients with ALD and sepsis. Keywords: Glutathione, Alcoholic liver disease, Sepsis, Antioxidants, Intensive care unit, Intravenous
... The final component of the Healthspan protocol was micronutrient therapy in the form of both IV and IM supplementation. Micronutrient therapy can have a variety of effects based on the specific micronutrients administered, with benefits including, though not limited to, antioxidant protection, glucose homeostasis, amino acid synthesis, reduced hypertension, and improved cognitive function [48][49][50][51][52]. These micronutrients can work both alone and in conjunction with the other therapies in the Healthspan protocol, further enhancing the wellness-centric approach to health. ...
Wellness-centric proactive healthcare is increasingly sought after, with individuals frequently embracing complementary modalities to achieve this goal. In this six-month study, healthy adult participants (n = 25) received specific therapies, including whole-body cryotherapy, infrared sauna, and photobiomodulation, along with guidance on physical activity, diet, and alcohol intake. Serum biomarkers were measured for all participants, while a subset also received biometric assessments for body composition (n = 10) and heart rate variability (n = 7). Over the course of the study (mean (SD) follow-up days = 174 (130)), participants exhibited significant improvements in health. LDL cholesterol (−9.77 (15.43) md/dL) and hsCRP (−1.75 (2.66) mg/L) decreased significantly (p < 0.05). HbA1c increased slightly (p < 0.05), but the effect size was small (0.12 (0.13)%). The body composition subset lost overall body weight (−3.29 (3.75) kg), primarily body fat, while preserving lean muscle mass (p < 0.05). Heart rate variability increased for those with existing cardiovascular risk factors (p < 0.05). In conclusion, participation in the multimodal Healthspan protocol is associated with substantial improvements in health-related biomarkers and biometrics.
... After that, the patients were treated with carbidopa-levodopa. Intravenous glutathione was associated with marked improvement in all patients, and resulted in a 42% reduction in disability [10]. ...
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.
... Glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) play a pivotal role for oxidative stress defense [105,106]. Various clinical studies showed that glutathione acts as a detoxifying and antioxidant agent [107][108][109][110][111][112][113]. Glutathione is a substrate for GPx and thereby reduces lipid peroxides. ...
Portulaca oleracea L. (P. oleracea) or purslane is a plant from the Portulacaceae family, which is used as food and traditional medicine for various diseases. This review article provides comprehensive information on the antioxidant, immunomodulatory, and anti-inflammatory properties of P. oleracea and its constituents. The literature survey of the different databases until the end of June 2023 was explored based on the keywords including the “P. oleracea, purslane, anti-inflammatory, immunomodulatory, and antioxidant properties.” The plant contains flavonoids, alkaloids, terpenoids, fatty acids, vitamins, minerals, and some other compounds. The results indicated that P. oleracea and its constituents showed anti-inflammatory and immunomodulatory properties through reduction of inflammatory mediators including interferon gama (IFN-γ), interleukin (IL)-10, IL-4, tumor necrosis factor-alpha (TNF-α), and nitric oxide. Improvement in cytokines’ serum levels (IFN-γ, IL-10, and IL-4) and increased IgG and IgM serum levels, as well as reduction of IgE, phospholipase A2, and total protein were demonstrated for P. oleracea. The plant and its constituents also improved oxidative stress by reduction of oxidant and increase of antioxidant markers. P. oleracea could be considered as an effective remedy for various inflammatory and immune diseases.
... Both in vitro and in vivo experiments confirmed that restoring levels of glutathione in PD patients represents a promising strategy to slow down the progression of the disease (Pradhan et al. 2020). PD patients were administrated with glutathione (two 600 mg doses twice a day for 30 days) intravenously (to avoid glutathione degradation in the gastrointestinal tract) (Sechi et al. 1996). GSH therapy improved the performance of patients, with nearly half a decline in disability of patients which lasted for about three months after interrupted therapy. ...
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.
... GSH is easily oxidized, showing a short half-life in plasma (<3 min). Moreover, GSH does not efficiently cross cell membranes requiring elevated quantities to gain therapeutic concentrations [166]. Although digestive peptidases can degrade oral GSH showing no change in GSH concentrations or oxidative stress parameters [167], some clinical studies found substantial increases in the body's GSH stores under different administrations. ...
Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson’s disease.
... Intravenous GSH has a short half-life but has shown to be effective in several diseases. For example, the GSH intravenous administration in patients with Parkinson's disease determined significant improvements, which lasted for 2-4 months after the administration (26). Also oral administration, although with conflicting results, resulted in increased serum GSH levels with reduced oxidative stress and beneficial effects in several diseases (27, 28). ...
Glutathione is a tripeptide synthesized at cytosolic level, that exists in cells in a reduced form (thiol-reduced-GSH-) and in an oxidized form (disulfide-oxidized). The antioxidant function of GSH has led to speculation about its therapeutic role in numerous chronic diseases characterized by altered redox balance and reduced GSH levels, including, for instance, neurodegenerative disorders, cancer, and chronic liver diseases. Among these latter, non-alcoholic fatty liver disease (NAFLD), characterized by lipid accumulation in hepatocytes, in the absence of alcohol abuse or other steatogenic factors, is one of the most prevalent. The umbrella term NAFLD includes the pure liver fat accumulation, the so-called hepatic steatosis or non-alcoholic fatty liver, and the progressive form with inflammation, also known as non-alcoholic steatohepatitis, which is related to the increase in oxidative stress and reactive oxygen species, eventually leading to liver fibrosis. Although the pathogenetic role of oxidative stress in these diseases is well established, there is still limited evidence on the therapeutic role of GSH in such conditions. Hence, the aim of this review is to depict the current molecular and pharmacological knowledge on glutathione, focusing on the available studies related to its therapeutic activity in NAFLD.
... Sechi et al. administered glutathione intravenously (600 mg twice daily for 30 days) to subjects with Parkinson's disease, and reported significant improvements, which lasted for 2-4 months even after ceasing the therapy. 97 In a case report a 61 year old man with Parkinson's disease treated with a complex protocol consisting of a gluten-free diet and dietary supplements (such as N-acetylcysteine and Silybum), and glutathione injections (1400 mg) administered twice, or three times weekly also reported symptom improvement. 98 Finally, preliminary cellular research using glutathione monoesters has been shown to be an effective delivery agent of glutathione due to improved bioavailability. ...
Glutathione is a tripeptide found in many tissues which plays a pivotal role in critical physiological processes such as maintenance of redox balance, reduction of oxidative stress by enhancement of metabolic detoxification of both xenobiotic and endogenous compounds, and regulation of immune system function. Glutathione depletion is associated with many chronic degenerative diseases and loss of function with aging and altered glutathione metabolism has been implicated in central nervous system diseases, frailty and sarcopenia, infected state, chronic liver diseases, metabolic diseases, pulmonary and cardiovascular diseases. Therefore, the glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Here we describe the main pharmacological aspects of glutathione, focusing on its synthesis and role in several vital functions including antioxidant defense, detoxification of xenobiotics and modulation of immune function and fibrogenesis and the clinical implications of its depletion and we discuss the different strategies for increasing glutathione cellular levels either by providing specific precursors and cofactors or directly administering the tripeptide.
... 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.
