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Lijing Xin, Ralf Mekle, Margot Fournier, Philipp S. Baumann, Carina Ferrari, Luis Alameda, Raoul Jenni, Huanxiang Lu, Benoit Schaller, Michel Cuenod, Philippe Conus, Rolf Gruetter, Kim Q. Do, Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis, Schizophrenia Bulletin, Volume 42, Issue 5, September 2016, Pages 1185–1196, https://doi.org/10.1093/schbul/sbw038
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Abstract
Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the γ-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu.
Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells.
Significantly lower [GSH mPFC ] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSH mPFC ] and blood GPx activities correlate positively in controls ( P = .021), but negatively in patients ( P = .039). In GCLC low-risk genotypes, [Glu mPFC ] are lower in patients, while it is not the case for high-risk genotypes.
GCLC high-risk genotypes are associated with low [GSH mPFC ], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.
- oxidative stress
- oxidation
- polymorphism
- glutathione
- homeostasis
- blood cells
- catalysis
- diencephalon
- genes
- genotype
- glutamate-cysteine ligase
- glutathione reductase
- magnetic resonance spectroscopy
- oxidation-reduction
- peroxidases
- prefrontal cortex
- psychotic disorders
- schizophrenia
- brain
- enzymes
- glutamate
- stratification