Abstract
Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer’s disease (AD). The main endogenous antioxidant, glutathione (GSH), has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH levels as a therapeutic target to treat these conditions include the administration of GSH itself, and low toxicity forms of the limiting amino acid for GSH synthesis; cysteine. However, passive GSH uptake is limited due to an unfavourable concentration gradient between the plasma and cytosol. Similarly, cysteine prodrugs have demonstrated limited efficacy to elevate depleted GSH levels in several in vivo and in vitro models of disease. It has been suggested that the decline in GSH levels in AD, may be associated with down regulation of GSH homeostasis rather than substrate limitation. Cellular GSH homeostasis is regulated by non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL), which is responsible for the synthesis of the GSH precursor γ-glutamylcysteine (GGC). In conditions involving down regulated GSH homeostasis, GGC serves as a crucialrate-limiting substrate for GSH synthetase, the main enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide, GSH. In this review, we focus on the therapeutic potential of GGC to elevate cellular GSH levels. We also discuss the efficacy of GGC prodrugs which would be taken up and converted by the unregulated GS to GSH, and the administration of modified GSH compounds, such as GSH esters that could potentially overcome the concentration gradient that prohibits passive GSH uptake, in AD.
Keywords: Alzheimer’s disease, antioxidants, dementia, glutathione, oxidative stress.
Current Alzheimer Research
Title:Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer`s Disease
Volume: 12 Issue: 4
Author(s): Nady Braidy, Martin Zarka, Jeffrey Welch and Wallace Bridge
Affiliation:
Keywords: Alzheimer’s disease, antioxidants, dementia, glutathione, oxidative stress.
Abstract: Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer’s disease (AD). The main endogenous antioxidant, glutathione (GSH), has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH levels as a therapeutic target to treat these conditions include the administration of GSH itself, and low toxicity forms of the limiting amino acid for GSH synthesis; cysteine. However, passive GSH uptake is limited due to an unfavourable concentration gradient between the plasma and cytosol. Similarly, cysteine prodrugs have demonstrated limited efficacy to elevate depleted GSH levels in several in vivo and in vitro models of disease. It has been suggested that the decline in GSH levels in AD, may be associated with down regulation of GSH homeostasis rather than substrate limitation. Cellular GSH homeostasis is regulated by non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL), which is responsible for the synthesis of the GSH precursor γ-glutamylcysteine (GGC). In conditions involving down regulated GSH homeostasis, GGC serves as a crucialrate-limiting substrate for GSH synthetase, the main enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide, GSH. In this review, we focus on the therapeutic potential of GGC to elevate cellular GSH levels. We also discuss the efficacy of GGC prodrugs which would be taken up and converted by the unregulated GS to GSH, and the administration of modified GSH compounds, such as GSH esters that could potentially overcome the concentration gradient that prohibits passive GSH uptake, in AD.
Export Options
About this article
Cite this article as:
Braidy Nady, Zarka Martin, Welch Jeffrey and Bridge Wallace, Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer`s Disease, Current Alzheimer Research 2015; 12 (4) . https://dx.doi.org/10.2174/1567205012666150302160308
DOI https://dx.doi.org/10.2174/1567205012666150302160308 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Reversal of Cardiac Iron Loading and Dysfunction in Thalassemic Mice by Curcuminoids
Medicinal Chemistry Bioinformatic Screening of Autoimmune Disease Genes and Protein Structure Prediction with FAMS for Drug Discovery
Protein & Peptide Letters Topical Chemoprevention of Skin Cancers with Phytochemicals
Current Cancer Therapy Reviews Topics of Physiological and Pathophysiological Functions of Lymphatics
Current Molecular Medicine Building Better Chimeric Antigen Receptors for Adoptive T Cell Therapy
Current Gene Therapy Pitfalls and Solutions for the Validation of Novel Drugs in Animal Models of Disease
Current Immunology Reviews (Discontinued) The Antisense Oligonucleotide Trabedersen (AP 12009) for the Targeted Inhibition of TGF-β2
Current Pharmaceutical Biotechnology In Vivo, Cardiac-Specific Knockdown of a Target Protein, Malic Enzyme- 1, in Rat via Adenoviral Delivery of DNA for Non-Native miRNA
Current Gene Therapy Does It Make Sense that Diabetes is Reciprocally Associated with Periodontal Disease?
Endocrine, Metabolic & Immune Disorders - Drug Targets Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer
Current Molecular Medicine Binding Sites of Amyloid β-Peptide in Cell Plasma Membrane and Implications for Alzheimers Disease
Current Protein & Peptide Science Celecoxib A Selective COX-2 Inhibitor Mitigates Fibrosis but not Pneumonitis Following Lung Irradiation: A Histopathological Study
Current Drug Therapy Sesquiterpenoids from Eupatorium Serotinum
The Natural Products Journal Salicylanilide Ester Prodrugs as Potential Antimicrobial Agents - a Review
Current Pharmaceutical Design Highlights in Peptide Nanoparticle Carriers Intended to Oral Diseases
Current Topics in Medicinal Chemistry In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells
Current Cancer Drug Targets Genetic Approaches for Antigen-Selective Cell Therapy
Current Gene Therapy Interactome Analysis of the Differentially Expressed Proteins in Uterine Leiomyoma
Anti-Cancer Agents in Medicinal Chemistry Zinc, Metallothioneins and Longevity: Interrelationships with Niacin and Selenium
Current Pharmaceutical Design Cytokine Network: New Targeted Therapy for Pancreatic Cancer
Current Pharmaceutical Design