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

Published:September 27, 2011DOI:https://doi.org/10.1016/j.biopsych.2011.07.035

      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.

      Key Words

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      Linked Article

      • N-Acetylcysteine for the Treatment of Glutathione Deficiency and Oxidative Stress in Schizophrenia
        Biological PsychiatryVol. 71Issue 11
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          Despite decades of intense research and development, current treatments for schizophrenia (SZ) have not only met with limited efficacy but are also often associated with serious side effects, justifying the heightened interest in the development of alternate therapies (1). With mounting experimental evidence implicating glutathione (GSH) deficiency and increased oxidative stress in the pathophysiology of most major psychiatric disorders (2), novel neuroprotective strategies that aim to limit oxidative stress-mediated cellular damage in such disorders, including SZ, are being increasingly scrutinized (2,3).
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