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.
(Less)
- author
- Duarte, Joao Miguel das Neves
LU
; Kulak, Anita
; Gholam-Razaee, Mehdi Mohammad
; Cuenod, Michel
; Gruetter, Rolf
and Do, Kim Quang
- publishing date
- 2012-06-01
- 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
- Elsevier
- external identifiers
-
- pmid:21945305
- 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
- 2024-04-28 21:55:14
@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}},
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}},
language = {{eng}},
month = {{06}},
number = {{11}},
pages = {{14--1006}},
publisher = {{Elsevier}},
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}},
doi = {{10.1016/j.biopsych.2011.07.035}},
volume = {{71}},
year = {{2012}},
}