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NADPH oxidase mediates depressive behavior induced by chronic stress in mice

Title
NADPH oxidase mediates depressive behavior induced by chronic stress in mice
Authors
Seo J.-S.Park J.-Y.Choi J.Kim T.-K.Shin J.-H.Lee J.-K.Han P.-L.
Ewha Authors
한평림
SCOPUS Author ID
한평림scopus
Issue Date
2012
Journal Title
Journal of Neuroscience
ISSN
0270-6474JCR Link
Citation
vol. 32, no. 28, pp. 9690 - 9699
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Stress is a potent risk factor for depression, yet the underlying mechanism is not clearly understood. In the present study, we explored the mechanism of development and maintenance of depression in a stress-induced animal model. Mice restrained for 2 h daily for 14 d showed distinct depressive behavior, and the altered behavior persisted for >3 months in the absence of intervention. Acute restraint induced a surge of oxidative stress in the brain, and stress-induced oxidative stress progressively increased with repetition of stress. In vitro, the stress hormone glucocorticoid generated superoxide via upregulation of NADPH oxidase. Consistently, repeated restraints increased the expression of the key subunits of NADPH oxidase, p47phox and p67phox, in the brain. Moreover, stressed brains markedly upregulated the expression of p47phox to weak restress evoked in the poststress period, and this molecular response was reminiscent of amplified ROS surge to restress. Pharmacological inhibition of NADPH oxidase by the NADPH oxidase inhibitor apocynin during the stress or poststress period completely blocked depressive behavior. Consistently, heterozygous p47phox knock-out mice (p47phox +/-) or molecular inhibition of p47phox with Lenti shRNA-p47phox in the hippocampus suppressed depressive behavior. These results suggest that repeated stress promotes depressive behavior through the upregulation of NADPH oxidase and the resultant metabolic oxidative stress, and that the inhibition of NADPH oxidase provides beneficial antidepression effects. © 2012 the authors.
DOI
10.1523/JNEUROSCI.0794-12.2012
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