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Open AccessArticle

Sp1-Mediated Prdx6 Upregulation Leads to Clasmatodendrosis by Increasing Its aiPLA2 Activity in the CA1 Astrocytes in Chronic Epilepsy Rats

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Ji-Eun Kim

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Duk-Shin Lee

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Tae-Cheon Kang

Antioxidants 2022, 11(10), 1883; https://doi.org/10.3390/antiox11101883 - 23 Sep 2022

Cited by 3 | Viewed by 901

Abstract

Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood. Peroxiredoxin-6 (Prdx6), the “non-selenium glutathione peroxidase (NSGPx)”, is the only member of the 1-cysteine peroxiredoxin family. Unlike the other Prdx family, Prdx6 has multiple [...] Read more.

Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood. Peroxiredoxin-6 (Prdx6), the “non-selenium glutathione peroxidase (NSGPx)”, is the only member of the 1-cysteine peroxiredoxin family. Unlike the other Prdx family, Prdx6 has multiple functions as glutathione peroxidase (GPx) and acidic calcium-independent phospholipase (aiPLA2). The present study shows that Prdx6 was upregulated in CA1 astrocytes in chronic epilepsy rats. 2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and N-acetylcysteine (NAC, a precursor of glutathione) ameliorated clasmatodendrosis accompanied by reduced Prdx6 level in CA1 astrocytes. Specificity protein 1 (Sp1) expression was upregulated in CA1 astrocyte, which was inhibited by mithramycin A (MMA). MMA alleviated clasmatodendrosis and Prdx6 upregulation. Sp1 expression was also downregulated by CDDO-Me and NAC. Furthermore, 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) attenuated clasmatodendrosis without affecting Prdx6 expression. All chemicals shortened spontaneous seizure duration but not seizure frequency and behavioral seizure severity in chronic epilepsy rats. Therefore, our findings suggest that Sp1 activation may upregulate Prdx6, whose aiPLA2 activity would dominate over GPx activity in CA1 astrocytes and may lead to prolonged seizure activity due to autophagic astroglial degeneration. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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Open AccessArticle

Dipeptide of ψ-GSH Inhibits Oxidative Stress and Neuroinflammation in an Alzheimer’s Disease Mouse Model

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Abbas Raza

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Wei Xie

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Kwan-Hyun Kim

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Venkateshwara Rao Dronamraju

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Jessica Williams

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Robert Vince

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Swati S. More

Antioxidants 2022, 11(6), 1075; https://doi.org/10.3390/antiox11061075 - 28 May 2022

Cited by 3 | Viewed by 1246

Abstract

Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical [...] Read more.

Supplementation of glutathione (GSH) levels through varying formulations or precursors has thus far appeared to be a tenable strategy to ameliorate disease-associated oxidative stress. Metabolic liability of GSH and its precursors, i.e., hydrolysis by the ubiquitous γ-glutamyl transpeptidase (γ-GT), has limited successful clinical translation due to poor bioavailability. We addressed this problem through the design of γ-GT-resistant GSH analogue, ψ-GSH, which successfully substituted in GSH-dependent enzymatic systems and also offered promise as a therapeutic for Alzheimer’s disease (AD). With the aim to improve its bioavailability, we studied the utility of a ψ-GSH precursor, dipeptide 2, as a potential AD therapeutic. Compound 2 retains the γ-GT stable ureide linkage and the thiol group for antioxidant property. By engaging glutathione synthetase, compound 2 was able to generate ψ-GSH in vivo. It was found to be a modest cofactor of glutathione peroxidase and prevented cytotoxicity of Aβ^1–42-aggregates in vitro. Studies of compound 2 in an acute AD model generated by intracerebroventricular injection of Aβ^1–42 showed cognitive benefits, which were augmented by its combination with glycine along with mitigation of oxidative stress and inflammatory pathology. Collectively, these results support further optimization and evaluation of ψ-GSH dipeptide as a potential therapeutic in transgenic AD models. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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Review

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Open AccessReview

How to Increase Cellular Glutathione

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Antioxidants 2023, 12(5), 1094; https://doi.org/10.3390/antiox12051094 - 13 May 2023

Viewed by 666

Abstract

Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly [...] Read more.

Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly reduced, making cells more susceptible to oxidative damage. Therefore, there is a growing interest in determining the best method(s) to increase cellular glutathione for both disease prevention and treatment. This review summarizes the major strategies for successfully increasing cellular GSH stores. These include GSH itself, its derivatives, NRf-2 activators, cysteine prodrugs, foods, and special diets. The possible mechanisms by which these molecules can act as GSH boosters, their related pharmacokinetic issues, and their advantages and disadvantages are discussed. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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Open AccessReview

Cellular Compartmentalization, Glutathione Transport and Its Relevance in Some Pathologies

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Héctor Vázquez-Meza

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María Magdalena Vilchis-Landeros

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Melissa Vázquez-Carrada

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Daniel Uribe-Ramírez

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Deyamira Matuz-Mares

Antioxidants 2023, 12(4), 834; https://doi.org/10.3390/antiox12040834 - 29 Mar 2023

Viewed by 647

Abstract

Reduced glutathione (GSH) is the most abundant non-protein endogenous thiol. It is a ubiquitous molecule produced in most organs, but its synthesis is predominantly in the liver, the tissue in charge of storing and distributing it. GSH is involved in the detoxification of [...] Read more.

Reduced glutathione (GSH) is the most abundant non-protein endogenous thiol. It is a ubiquitous molecule produced in most organs, but its synthesis is predominantly in the liver, the tissue in charge of storing and distributing it. GSH is involved in the detoxification of free radicals, peroxides and xenobiotics (drugs, pollutants, carcinogens, etc.), protects biological membranes from lipid peroxidation, and is an important regulator of cell homeostasis, since it participates in signaling redox, regulation of the synthesis and degradation of proteins (S-glutathionylation), signal transduction, various apoptotic processes, gene expression, cell proliferation, DNA and RNA synthesis, etc. GSH transport is a vital step in cellular homeostasis supported by the liver through providing extrahepatic organs (such as the kidney, lung, intestine, and brain, among others) with the said antioxidant. The wide range of functions within the cell in which glutathione is involved shows that glutathione’s role in cellular homeostasis goes beyond being a simple antioxidant agent; therefore, the importance of this tripeptide needs to be reassessed from a broader metabolic perspective. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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Open AccessReview

Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase

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Antioxidants 2022, 11(2), 296; https://doi.org/10.3390/antiox11020296 - 31 Jan 2022

Cited by 4 | Viewed by 2152

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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Open AccessReview

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

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Antioxidants 2021, 10(11), 1703; https://doi.org/10.3390/antiox10111703 - 27 Oct 2021

Cited by 14 | Viewed by 1964

Abstract

Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical [...] Read more.

Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical glutathione (GSH). A large body of pre-clinical data has suggested the possibility of notable GSH-deficit in a subgroup of patients with schizophrenia. Nevertheless, studies of intracortical GSH are not conclusive in this regard. In this review, we highlight the recent ultra-high field magnetic resonance spectroscopic studies linking GSH to critical outcome measures across various stages of schizophrenia. We discuss the methodological steps required to conclusively establish or refute the persistence of GSH-deficit subtype and clarify the role of the central antioxidant system in disrupting the brain structure and connectivity in the early stages of schizophrenia. We propose in-vivo GSH quantification for patient selection in forthcoming antioxidant trials in psychosis. This review offers directions for a promising non-dopaminergic early intervention approach in schizophrenia. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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Open AccessReview

In Vivo Brain GSH: MRS Methods and Clinical Applications

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Maria Camilla Rossi Espagnet

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Luca Pasquini

Antioxidants 2021, 10(9), 1407; https://doi.org/10.3390/antiox10091407 - 01 Sep 2021

Cited by 18 | Viewed by 2766

Abstract

Glutathione (GSH) is an important antioxidant implicated in several physiological functions, including the oxidation−reduction reaction balance and brain antioxidant defense against endogenous and exogenous toxic agents. Altered brain GSH levels may reflect inflammatory processes associated with several neurologic disorders. An accurate and reliable [...] Read more.

Glutathione (GSH) is an important antioxidant implicated in several physiological functions, including the oxidation−reduction reaction balance and brain antioxidant defense against endogenous and exogenous toxic agents. Altered brain GSH levels may reflect inflammatory processes associated with several neurologic disorders. An accurate and reliable estimation of cerebral GSH concentrations could give a clear and thorough understanding of its metabolism within the brain, thus providing a valuable benchmark for clinical applications. In this context, we aimed to provide an overview of the different magnetic resonance spectroscopy (MRS) technologies introduced for in vivo human brain GSH quantification both in healthy control (HC) volunteers and in subjects affected by different neurological disorders (e.g., brain tumors, and psychiatric and degenerative disorders). Additionally, we aimed to provide an exhaustive list of normal GSH concentrations within different brain areas. The definition of standard reference values for different brain areas could lead to a better interpretation of the altered GSH levels recorded in subjects with neurological disorders, with insights into the possible role of GSH as a biomarker and therapeutic target. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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Open AccessReview

Glutathione in the Nervous System as a Potential Therapeutic Target to Control the Development and Progression of Amyotrophic Lateral Sclerosis

by

Kiyoung Kim

Antioxidants 2021, 10(7), 1011; https://doi.org/10.3390/antiox10071011 - 23 Jun 2021

Cited by 17 | Viewed by 3537

Abstract

Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder that affects the motor neurons responsible for regulating muscle movement. However, the molecular pathogenic mechanisms of ALS remain poorly understood. A deficiency in the antioxidant tripeptide glutathione (GSH) in the nervous system appears to [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder that affects the motor neurons responsible for regulating muscle movement. However, the molecular pathogenic mechanisms of ALS remain poorly understood. A deficiency in the antioxidant tripeptide glutathione (GSH) in the nervous system appears to be involved in several neurodegenerative diseases characterized by the loss of neuronal cells. Impaired antioxidant defense systems, and the accumulation of oxidative damage due to increased dysfunction in GSH homeostasis are known to be involved in the development and progression of ALS. Aberrant GSH metabolism and redox status following oxidative damage are also associated with various cellular organelles, including the mitochondria and nucleus, and are crucial factors in neuronal toxicity induced by ALS. In this review, we provide an overview of the implications of imbalanced GSH homeostasis and its molecular characteristics in various experimental models of ALS. Full article

(This article belongs to the Special Issue Glutathione in Health and Disease)

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