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ludc web

Joao Duarte

Principal investigator

ludc web

N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development

Author

  • Joao Miguel das Neves Duarte
  • Anita Kulak
  • Mehdi Mohammad Gholam-Razaee
  • Michel Cuenod
  • Rolf Gruetter
  • Kim Quang Do

Summary, in English

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.

Publishing year

2012-06-01

Language

English

Pages

14-1006

Publication/Series

Biological Psychiatry

Volume

71

Issue

11

Document type

Journal article

Publisher

Elsevier

Keywords

  • Acetylcysteine
  • Alanine
  • Animals
  • Aspartic Acid
  • Cerebral Cortex
  • Disease Models, Animal
  • Free Radical Scavengers
  • Glutamate-Cysteine Ligase
  • Glutamic Acid
  • Glutamine
  • Glutathione
  • Inositol
  • Lactic Acid
  • Longitudinal Studies
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Knockout
  • Schizophrenia
  • Journal Article
  • Research Support, Non-U.S. Gov't

Status

Published

ISBN/ISSN/Other

  • ISSN: 0006-3223