Glutathione Pathways in the Brain

Abstract

The antioxidant glutathione (GSH) is essential for the cellular detoxification of reactive oxygen species in brain cells. A compromised GSH system in the brain has been connected with the oxidative stress occuring in neurological diseases. Recent data demonstrate that besides intracellular functions GSH has also important extracellular functions in brain. In this respect astrocytes appear to play a key role in the GSH metabolism of the brain, since astroglial GSH export is essential for providing GSH precursors to neurons. Of the different brain cell types studied in vitro only astrocytes release substantial amounts of GSH. In addition, during oxidative stress astrocytes efficiently export glutathione disulfide (GSSG). The multidrug resistance protein 1 participates in both the export of GSH and GSSG from astrocytes. This review focuses on recent results on the export of GSH and GSSG from brain cells as well as on the functions of extracellular GSH in the brain. In addition, implications of disturbed GSH pathways in brain for neurodegenerative diseases will be discussed.

Ethyl-Eicosapentaenoic Acid in First-Episode Psychosis. A 1H-MRS Study

“…Interestingly, the changes in GSH and GLX were positively correlated (r ¼ 0.64, p ¼ 0.01), indicating that the metabolic changes of these two metabolites were tightly coupled. This would be expected for metabolites involved in the same metabolic pathway (Dringen and Hirrlinger, 2003) when neither is at limiting concentrations for subsequent metabolic processes. Another potential explanation for the linked change in 1H-MRS signals may be that the changes occur at the site of production of both metabolites.…”

“…Another potential explanation for the linked change in 1H-MRS signals may be that the changes occur at the site of production of both metabolites. Glutathione is mainly produced by the reaction of glutamate with cysteine and glycine, a process occurring predominantly in astrocytes (Dringen and Hirrlinger, 2003). Astrocytes are also responsible for the conversion of glutamate into glutamine (Hertz, 2004;Hertz and Zielke, 2004).…”

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

“…However, the results of human clinical trials are inconsistent in slowing down disease progression, but there is still hope that improved antioxidant mimetics that better target ROS production pathways might prove beneficial. Glutathione (GSH) is considered the main regulator of redox balance in the cellular milieu due to its capacity for detoxifying noxious molecules (Byrd et al, 2004;Dringen, 2000;Dringen and Hirrlinger, 2003). Upregulation of GSH levels has been achieved using oral administration of N-acetyl-Lcysteine (NAC), which results in increased brain GSH level, brain synaptic mitochondrial complex I activity (Banaclocha, 2000), and also increased neuronal survival and behavioral read-outs in MPTP-induced parkinsonian degeneration in mice (Berman et al, 2011;Clark et al, 2010).…”

Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

“…Being the main antioxidant in the brain (Dringen and Hirrlinger, 2003), glutathione protects cells from damage by reactive oxygen species originating partly from dopamine metabolism. Decreased glutathione levels might lead to degenerative processes in the surroundings of dopaminergic terminals with loss of connectivity as a result.…”