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

Duarte, Joao Miguel das Neves LU ; Kulak, Anita; Gholam-Razaee, Mehdi Mohammad; Cuenod, Michel; Gruetter, Rolf and Do, Kim Quang (2012) In Biological Psychiatry 71(11). p.14-1006
Abstract

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,... (More)

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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author
publishing date
type
Contribution to journal
publication status
published
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
in
Biological Psychiatry
volume
71
issue
11
pages
9 pages
publisher
Society of Biological Psychiatry Published by Elsevier Inc.
external identifiers
  • scopus:84861039574
ISSN
0006-3223
DOI
10.1016/j.biopsych.2011.07.035
language
English
LU publication?
no
id
840a4b27-4cc9-4d52-99af-70ff6233b55c
date added to LUP
2017-10-19 15:11:05
date last changed
2017-10-30 15:57:37
@article{840a4b27-4cc9-4d52-99af-70ff6233b55c,
  abstract     = {<p>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).</p><p>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.</p><p>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.</p><p>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.</p>},
  author       = {Duarte, Joao Miguel das Neves and Kulak, Anita and Gholam-Razaee, Mehdi Mohammad and Cuenod, Michel and Gruetter, Rolf and Do, Kim Quang},
  issn         = {0006-3223},
  keyword      = {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},
  language     = {eng},
  month        = {06},
  number       = {11},
  pages        = {14--1006},
  publisher    = {Society of Biological Psychiatry Published by Elsevier Inc.},
  series       = {Biological Psychiatry},
  title        = {N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development},
  url          = {http://dx.doi.org/10.1016/j.biopsych.2011.07.035},
  volume       = {71},
  year         = {2012},
}