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N-Acetylcysteine Normalizes Neurochemical Changes in the Glutathione-Deficient Schizophrenia Mouse Model During Development
Open accessAbstract
Background Glutathione (GSH) is the major cellular redox-regulator and antioxidant. Redox-imbalance due to genetically impaired GSH synthesis is among the risk factors for schizophrenia. Here we used a mouse model with chronic GSH deficit induced by knockout (KO) of the key GSH-synthesizing enzyme, glutamate-cysteine ligase modulatory subunit (GCLM).Methods With high-resolution magnetic resonance spectroscopy at 14.1 T, we determined the neurochemical profile of GCLM-KO, heterozygous, and wild-type mice in anterior cortex throughout development in a longitudinal study design.Results Chronic GSH deficit was accompanied by an elevation of glutamine (Gln), glutamate (Glu), Gln/Glu, N-acetylaspartate, myo-Inositol, lactate, and alanine. Changes were predominantly present at prepubertal ages (postnatal days 20 and 30). Treatment with N-acetylcysteine from gestation on normalized most neurochemical alterations to wild-type level.Conclusions Changes observed in GCLM-KO anterior cortex, notably the increase in Gln, Glu, and Gln/Glu, were similar to those reported in early schizophrenia, emphasizing the link between redox imbalance and the disease and validating the model. The data also highlight the prepubertal period as a sensitive time for redox-related neurochemical changes and demonstrate beneficial effects of early N-acetylcysteine treatment. Moreover, the data demonstrate the translational value of magnetic resonance spectroscopy to study brain disease in preclinical models.
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“In mice with a weakened GSH synthesis (Gclm KO mice), NAC prevents PVI and PNN deficits induced by an oxidative insult during postnatal development (Cabungcal et al., 2013a), although it does not increase GSH levels because of the Gclm deletion (das Neves Duarte et al., 2012).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as das Neves Duarte et al., 2012
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Metadata
- Authors
- das Neves Duarte, J. M., Kulak, A., Gholam-Razaee, M. M., Cuenod, M., Gruetter, R., & Do, K. Q.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 71
- Issue
- 11
- Pages
- 1006-1014
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2171650204
- Cited by
- 124
- References
- 76
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 6 · 2019: 10 · 2018: 4 · 2017: 11 · 2016: 13 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 9
- FWCI
- 6.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation (310030)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (135736, 310030)
- Université de Genève
- Université de Lausanne
- Centre d'Imagerie BioMédicale
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- N-acetylcysteine, glutathione deficiency, schizophrenia, redox imbalance, neurochemical changes, glutamine, glutamate, N-acetylaspartate, myo-inositol, lactate, prepubertal development, anterior cortex, early treatment, mouse model
- MeSH terms
- Acetylcysteine, Alanine, Animals, Aspartic Acid, Cerebral Cortex, Disease Models, Animal, Glutamate-Cysteine Ligase, Glutamine, Glutathione, Inositol, Longitudinal Studies, Magnetic Resonance Spectroscopy, Schizophrenia, Free Radical Scavengers, Mice, Knockout, Glutamic Acid, Lactic Acid, Mice
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