The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GGC), Can Ameliorate Oxidative Damage and Neuroinflammation Induced by Aβ40 Oligomers in Human Astrocytes

Abstract

Glutathione (GSH) is one of the most abundant thiol antioxidants in cells. Many chronic and age-related diseases are associated with a decline in cellular GSH levels or impairment in the catalytic activity of the GSH biosynthetic enzyme glutamate cysteine ligase (GCL). γ-glutamylcysteine (GGC), a precursor to glutathione (GSH), can replenish depleted GSH levels under oxidative stress conditions, by circumventing the regulation of GSH biosynthesis and providing the limiting substrate. Soluble amyloid-β (Aβ) oligomers have been shown to induce oxidative stress, synaptic dysfunction and memory deficits which have been reported in Alzheimer’s disease (AD). Calcium ions, which are increased with age and in AD, have been previously reported to enhance the formation of Aβ 40 oligomers, which have been casually associated with the pathogenesis of the underlying neurodegenerative condition. In this study, we examined the potential beneficial effects of GGC against exogenous Aβ 40 oligomers on biomarkers of apoptosis and cell death, oxidative stress, and neuroinflammation, in human astrocytes. Treatment with Aβ 40 oligomers significantly reduced the cell viability and apoptosis of astrocyte brain cultures and increased oxidative modifications of DNA, lipids, and protein, enhanced pro-inflammatory cytokine release and increased the activity of the proteolytic matrix metalloproteinase enzyme, matric metalloproteinase (MMP)-2 and reduced the activity of MMP-9 after 24 h. Co-treatment of Aβ 40 oligomers with GGC at 200 μM increased the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) and led to significant increases in the levels of the total antioxidant capacity (TAC) and GSH and reduced the GSSG/GSH ratio. GGC also upregulated the level of the anti-inflammatory cytokine IL-10 and reduced the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and attenuated the changes in metalloproteinase activity in oligomeric Aβ 40 -treated astrocytes. Our data provides renewed insight on the beneficial effects of increased GSH levels by GGC in human astrocytes, and identifies yet another potential therapeutic strategy to attenuate the cytotoxic effects of Aβ oligomers in AD.

γ‐Glutamylcysteine Alleviates Ischemic Stroke‐Induced Neuronal Apoptosis by Inhibiting ROS‐Mediated Endoplasmic Reticulum Stress

“…Moreover, inflammation is a principal contributor to ischemic injury. γ-GC exerts an anti-inflammatory effect on AD and sepsis [23,32]. Therefore, in a future study, we can further explore whether γ-GC has the capacity to combat inflammation and inhibit ferroptosis.…”

“…It was first confirmed in 1983 that γ-GC, an intermediate dipeptide with a sulfhydryl group in the GSH synthesis pathway, could increase the levels of GSH in the kidney [20]. Further studies have demonstrated that γ-GC and its esterified form GCEE can protect against oxidative damage in a variety of cell types through catalysis by GSS to produce intracellular GSH [23,24,31]. Recent studies have shown that compared with NAC and GSH supplementation, γ-GC administration was more effective in preventing lipopolysaccharide-(LPS-) or cecal ligation and puncture-(CLP-) induced systemic inflammatory responses [32].…”

“…Liu et al found that dietary supplementation with γ-GC improved the spatial memory of Alzheimer's disease (AD) mice by increasing total GSH and reducing the levels of oxidative stress and nerve cell apoptosis [22]. A recent study showed that γ-GC exerts antioxidative and anti-inflammatory effects against oligomeric Aβ 40 -induced astrocyte injury [23]. Additionally, γ-GC has been shown to inhibit oxidative injury in endothelial cells [24].…”

Novel Antioxidant Therapy with the Immediate Precursor to Glutathione, γ-Glutamylcysteine (GGC), Ameliorates LPS-Induced Cellular Stress in In Vitro 3D-Differentiated Airway Model from Primary Cystic Fibrosis Human Bronchial Cells

“…Despite multiple clinical trials with current glutathione-based therapies, improved clinical outcomes in CF have not been achieved [6,7]. As a precursor to glutathione, GGC has been consistently shown to increase intracellular levels of glutathione in both in vivo and in vitro models [16][17][18][21][22][23][24], and to reduce inflammation and oxidative stress [19,43,44]. Recently, it was shown that GGC exhibits anti-inflammatory effects in an in vivo and in vitro mouse sepsis model [24].…”

Down syndrome as a genetic model to evaluate the role of oxidative stress and transsulfuration abnormalities in autism spectrum disorder: A 10‐year longitudinal cohort study

“…Glutathione protects the brain from oxidative stress, xenobiotics, and neuroinflammation (Braidy et al, ) and studies show that glutathione shortages have a negative impact on brain health and neurodevelopment (Forman, Zhang, & Rinna, ). In addition, glutathione is also involved in preventing toxins and deleterious compounds from entering the brain as glutathione is an integral part of the choroid plexus, which forms the blood–cerebral spinal fluid barrier (Kratzer et al, ).…”