Lijing Xin1, Ralf Mekle2, Margot Fournier3, Philipp S Baumann4, Carina Ferrari4, Luis Alameda4, Raoul Jenni4, Huanxiang Lu5, Benoit Schaller6, Michel Cuenod3, Philippe Conus7, Rolf Gruetter, Kim Q Do8. 1. Animal Imaging and Technology Core (AIT), Center for Biomedical Imaging (CIBM), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 2. Physikalisch-Technische Bundesanstalt, Berlin, Germany; 3. Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; 4. Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; 5. Institute of Surgical Technology and Biomechanics, University of Bern, Bern, Switzerland; 6. Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 7. Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; 8. Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital (CHUV), Lausanne, Switzerland; kim.do@chuv.ch.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes. CONCLUSIONS: GCLC high-risk genotypes are associated with low [GSHmPFC], 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.
BACKGROUND: 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. METHODS: Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosispatients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. RESULTS: Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes. CONCLUSIONS:GCLC high-risk genotypes are associated with low [GSHmPFC], 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 psychosispatients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.
Authors: René Gysin; Rudolf Kraftsik; Olivier Boulat; Pierre Bovet; Philippe Conus; Emily Comte-Krieger; Andrea Polari; Pascal Steullet; Martin Preisig; Tanja Teichmann; Michel Cuénod; Kim Q Do Journal: Antioxid Redox Signal Date: 2010-10-30 Impact factor: 8.401
Authors: Thomas W Sedlak; Leslie G Nucifora; Minori Koga; Lindsay S Shaffer; Cecilia Higgs; Teppei Tanaka; Anna M Wang; Jennifer M Coughlin; Peter B Barker; Jed W Fahey; Akira Sawa Journal: Mol Neuropsychiatry Date: 2018-04-17
Authors: Ragy R Girgis; Seth Baker; Xiangling Mao; Roberto Gil; Daniel C Javitt; Joshua T Kantrowitz; Meng Gu; Daniel M Spielman; Najate Ojeil; Xiaoyan Xu; Anissa Abi-Dargham; Dikoma C Shungu; Lawrence S Kegeles Journal: Psychiatry Res Date: 2019-03-12 Impact factor: 3.222
Authors: Yeni Kim; Krishna C Vadodaria; Zsolt Lenkei; Tadafumi Kato; Fred H Gage; Maria C Marchetto; Renata Santos Journal: Antioxid Redox Signal Date: 2019-02-01 Impact factor: 8.401
Authors: Sina Hafizi; Tania Da Silva; Jeffrey H Meyer; Michael Kiang; Sylvain Houle; Gary Remington; Ivana Prce; Alan A Wilson; Pablo M Rusjan; Napapon Sailasuta; Romina Mizrahi Journal: Neuropsychopharmacology Date: 2018-04-13 Impact factor: 7.853
Authors: Caroline Demro; Laura Rowland; S Andrea Wijtenburg; James Waltz; James Gold; Emily Kline; Elizabeth Thompson; Gloria Reeves; L Elliot Hong; Jason Schiffman Journal: Psychiatry Res Date: 2017-07-24 Impact factor: 3.222
Authors: Kun Yang; Anouk Marsman; Subechhya Pradhan; Jennifer M Coughlin; Min Wang; Rebecca E Ward; Susanne Bonekamp; Emily B Ambinder; Cecilia P Higgs; Pearl K Kim; Jamie A Edwards; Mark Varvaris; Hongxing Wang; Sotirios Posporelis; Shuangchao Ma; Tsuyoshi Tsujimura; Richard A E Edden; Martin G Pomper; Thomas W Sedlak; Margot Fournier; David J Schretlen; Nicola G Cascella; Peter B Barker; Akira Sawa Journal: Mol Psychiatry Date: 2020-10-19 Impact factor: 15.992