In Vivo Brain GSH: MRS Methods and Clinical Applications

Abstract

Glutathione (GSH) is an important antioxidant implicated in several physiological functions, including the oxidation-reduction reaction balance and brain antioxidant defense against endogenous and exogenous toxic agents. Altered brain GSH levels may reflect inflammatory processes associated with several neurologic disorders. An accurate and reliable estimation of cerebral GSH concentrations could give a clear and thorough understanding of its metabolism within the brain, thus providing a valuable benchmark for clinical applications. In this context, we aimed to provide an overview of the different magnetic resonance spectroscopy (MRS) technologies introduced for in vivo human brain GSH quantification both in healthy control (HC) volunteers and in subjects affected by different neurological disorders (e.g., brain tumors, and psychiatric and degenerative disorders). Additionally, we aimed to provide an exhaustive list of normal GSH concentrations within different brain areas. The definition of standard reference values for different brain areas could lead to a better interpretation of the altered GSH levels recorded in subjects with neurological disorders, with insights into the possible role of GSH as a biomarker and therapeutic target.

Keywords: glutathione (GSH); magnetic resonance spectroscopy (MRS); neurological disorders.

Figure 1

Glutathione (GSH) metabolism within the nervous tissue. GSH is synthesized in the cytoplasm of neurons and glia from essential amino acids, and catabolized through hydrolysis in the cell membranes. GSH acts as a reducing agent by donating an electron to H₂O₂, leading to the formation of H₂O, O₂, and glutathione disulfide (GSSG), which is regenerated by glutathione reductase (GR) from NADPH. The transportation of GSH and essential metabolites is regulated by different transporters across cell membranes. Cys—cysteine; glu—glutamate; gln—glycine; met—methionine; homocys—homocysteine; MPR—multidrug resistance pump; γGT—γ-glutamyltransferase; γ-glucys—γ-glutamylcysteine; EAAT—excitatory amino acid transporter; SNAT—sodium-coupled neutral amino acid transporter; ASC—alanine, serine, and cysteine transport system.