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PLoS One. 2017 Jun 9;12(6):e0177940. doi: 10.1371/journal.pone.0177940. eCollection 2017.

Monoamine oxidase A upregulated by chronic intermittent hypoxia activates indoleamine 2,3-dioxygenase and neurodegeneration.

Author information

1
School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
2
Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
3
Eve Topf Center for Neurodegenerative Diseases Research, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Abstract

Co-morbid depression is prevalent in patients with obstructive sleep apnea. Here we report that monoamine oxidase A (MAO-A) plays pathogenic roles in the comorbidity. We found that chronic intermittent hypoxia significantly increased the MAO-A expression in the rat hippocampus and markedly decreased the dendritic length and spine density in the pyramidal neurons with less pre- and post-synaptic proteins. The MAO-A upregulation resulted in increased 5-hydroxyindoleacetic acid/serotonin ratio, oxidative stress, leading to NF-κB activation, inflammation and apoptosis. Also, the expression of cytokine-responsive indoleamine 2,3-dioxygenase-1 (IDO-1) was significantly augmented in hypoxia, resulting in increased kynurenine/tryptophan ratio and lowered serotonin level in the hippocampus. Moreover, depressive-like behaviors were observed in the hypoxic rat. Administration of M30, a brain-selective MAO-A inhibitor with iron-chelating properties, prior to hypoxic treatment prevented the aberrant changes in the hippocampus and depressive behavior. In human SH-SY5Y cells expressing MAO-A but not MAO-B, hypoxia significantly increased the MAO-A expression, which was blocked by M30 or clorgyline. Collectively, the MAO-A upregulation induced by chronic intermittent hypoxia plays significant pathogenic role in oxidative stress, inflammation and IDO-1 activation resulting in serotonin depletion and neurodegeneration.

PMID:
28599322
PMCID:
PMC5466431
DOI:
10.1371/journal.pone.0177940
[Indexed for MEDLINE]
Free PMC Article

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