Synthesis of the Antioxidant Glutathione in Neurons: Supply by Astrocytes of CysGly as Precursor for Neuronal Glutathione

A high astrocytic GSH content is essential to provide neighboring neurons with amino acid precursors for neuronal GSH synthesis.

“A high astrocytic GSH content of astrocytes is essential to provide neighboring neurons with amino acid precursors for neuronal GSH synthesis.”

The supply of cysteine as neuronal GSH precursor by astrocytes is strongly inhibited by the presence of the γGT inhibitor acivicin, demonstrating that γGT plays a central role in the supply of cysteine to neurons.

“The supply of cysteine as neuronal GSH precursor by astrocytes (Figure 1) is strongly inhibited by the presence of the γGT inhibitor acivicin (Dringen, Pfeiffer, et al. 1999), demonstrating that γGT plays a central role in the supply of cysteine to neurons.”

Exported GSH becomes substrate of the astrocytic ectoenzyme γGT which liberates the dipeptide CysGly.

“The exported GSH becomes substrate of the astrocytic ectoenzyme γGT which liberates the dipeptide CysGly.”

The cysteine supply by astrocytes is initiated by the export of GSH from astrocytes.

“The cysteine supply by astrocytes is initiated by the export of GSH from astrocytes (Dringen, Pfeiffer, et al. 1999; Wang and Cynader 2000)”

The amino acids cysteine and glycine liberated by hydrolysis are efficiently taken up by sodium-dependent transporters into neurons and can be used as substrates for neuronal GSH synthesis.

“The amino acids liberated by the hydrolysis, cysteine and glycine, are efficiently taken up by sodium‐dependent transporters into neurons (Aoyama and Nakaki 2013; Zafra and Giménez 2008) and can be used as substrates for neuronal GSH synthesis (Dringen, Pfeiffer, et al. 1999; Kranich et al. 1996).”

In co-cultures, the presence of astrocytes increases the GSH content in the cocultured neurons.

“Several groups have shown that in co‐cultures, the presence of astrocytes increases the GSH content in the cocultured neurons (Bolaños et al. 1996; Diaz‐Hernandez et al. 2005; Dringen, Pfeiffer, et al. 1999; Gegg et al. 2005; Pizzurro et al. 2014; Rathinam et al. 2012), demonstrating that the presence of astrocytes has a stimulating positive effect on the GSH content of neurons.”

Both the chemical reduction of extracellular cystine by GSH released from astrocytes and transfer via extracellular vesicles should not be affected by inhibitors of the astrocytic γGT or neuronal aminopeptidase N.

“However, both the chemical reduction of extracellular cystine by GSH released from astrocytes as well as transfer via extracellular vesicles should not be affected by inhibitors of the astrocytic γGT or neuronal aminopeptidase N, which were shown to be involved in the supply of cysteine to neurons (Dringen, Pfeiffer, et al. 1999) and in the use of CysGly by neurons (Dringen et al. 2001).”