N-Acetylcysteine Normalizes Neurochemical Changes in the Glutathione-Deficient Schizophrenia Mouse Model During Development

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• 作者：Joao Miguel das Neves Duarte^a ; ^b ; Anita Kulak^c ; Mehdi Mohammad Gholam-Razaee^d ; Michel Cuenod^c ; Rolf Gruetter^a ; ^e ; Kim Quang Do^c ; ^{kim.do@chuv.ch}
• 关键词：Glutathione ; MRS ; N-acetylcysteine ; neurochemical profile ; oxidative stress ; schizophrenia
• 刊名：Biological Psychiatry
• 出版年：2012
• 期刊代码：34_00063223
• 类别：med
• 出版时间：1 June, 2012
• 卷：71
• 期：11
• 页码：1006-1014
• 文件大小：794 K

摘要

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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.