Astrocytes Protect Against Copper-Catalysed Loss of Extracellular Glutathione

Abstract

Glutathione (GSH) is one of the major antioxidants in the brain. GSH is secreted by astrocytes and this extracellular GSH is used by neurones to maintain and increase their intracellular GSH levels. For efficient GSH trafficking between astrocytes and neurones, GSH needs to be maintained in the reduced form. In model systems, GSH trafficking has been shown to be essential for neuroprotection against a variety of stress conditions. Previously we and others have shown that GSH and thiols are unstable in cell culture media and are easily oxidised. In the present study it is shown that nanomolar concentrations of copper (II) ions can cause decay of GSH in cell culture media. Increased free or redox active copper has been implicated in a variety of diseases and degradation of extracellular GSH is a possible mechanism by which it exerts its harmful effects. Rat astrocytes, a human astrocytoma cell line and astrocyte-conditioned media, in the absence of cells, are able to retard this copper-catalysed decay of GSH and maintain GSH in its reduced form. The protective effect of astrocytes appears to be a combination of copper removing and antioxidant mechanisms. The importance of these protective mechanisms is discussed with regards to neurodegenerative diseases.

Gliopreventive effects of guanosine against glucose deprivation in vitro

“…The increase in GSH levels in glial cells confers protection against neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases [95,96]. Moreover, the tripeptide GSH constitutes a nonenzymatic scavenger and substrate for glutathione peroxidase [34,97]. Glucose deprivation induces a decrease in NADPH regeneration, a molecule that is required to maintain glutathione in a reduced form (GSH) via glutathione reductase [79,98].…”

Probing the coordination properties of glutathione with transition metal ions (Cr2+,Mn2+,Fe2+,Co2+, Ni2+,Cu2+,Zn2+,Cd2+,Hg2+) by density functional theory

“…However, excess copper can result in marked reactive oxygen species (ROS) formation that can damage lipids, nucleic acids and proteins [12,13]. Increased free or redox active copper can also lead to the degradation of extracellular GSH, by which it exerts its harmful effects [14]. Although zinc is essential for cellular function, sustained increases in free Zn 2+ levels are harmful.…”

Copper Accelerates Glycolytic Flux in Cultured Astrocytes

“…At least in co-cultures, astrocytes protect cerebellar neurones against copper toxicity [16]. In addition, astrocytes prevent the copper catalysed extracellular loss of GSH [19]. However, excess of copper has been reported to damage astrocytes.…”