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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Article info
Publication history
Published online: September 27, 2011
Accepted:
July 29,
2011
Received in revised form:
July 11,
2011
Received:
March 23,
2011
Footnotes
Authors JMdND and AK contributed equally to this work.
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- N-Acetylcysteine for the Treatment of Glutathione Deficiency and Oxidative Stress in SchizophreniaBiological PsychiatryVol. 71Issue 11
- PreviewDespite 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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