Glutathione Metabolism of the Brain—The Role of Astrocytes

Astrocytes have essential functions in the brain as partners of neurons in many metabolic and homeostatic processes. The metabolism of the tripeptide GSH (γ-L-glutamyl-L-cysteinyl-glycine) is an important example of a metabolic interaction between astrocytes and neurons. GSH is present in brain cells in millimolar concentrations and has essential functions as an antioxidant and as a substrate for detoxification reactions. A high GSH content protects astrocytes against oxidative stress and toxins and is therefore beneficial for the astrocytic self-defense that helps to maintain the essential functions of astrocytes in the brain and will enable astrocytes to eliminate potential toxins before they may reach other brain cells. In addition, astrocytes provide neurons with the amino acids required for GSH synthesis in a process that involves the export of GSH from astrocytes by the multidrug resistance protein 1, the extracellular processing of GSH via the astrocytic γ-glutamyl transpeptidase to generate the dipeptide cysteinyl-glycine, and the extracellular cleavage of this dipeptide by the neuronal ectopeptidase aminopeptidase N. As GSH export from astrocytes strongly depends on the cytosolic GSH concentration, a high astrocytic GSH content will also facilitate GSH release and thereby the supply of GSH precursors to neighboring neurons. In this article, we will give an overview of the current knowledge on the GSH metabolism of astrocytes, address how a high astrocytic GSH content can help to maintain brain functions, and discuss open questions and future perspectives of research on the functions of astrocytes in the GSH metabolism of the healthy and diseased brain.