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

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

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.

MeSH terms

  • Animals
  • Apoptosis
  • Brain / metabolism
  • Cell Line
  • Depression / metabolism
  • Enzyme Activation
  • Hippocampus / metabolism
  • Humans
  • Hypoxia / metabolism*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Male
  • Monoamine Oxidase / metabolism*
  • NF-kappa B / metabolism
  • Neurons / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Rats

Substances

  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • NF-kappa B
  • Monoamine Oxidase

Grant support

This work was supported by internal funding (104004440) granted by The University of Hong Kong and the General Research Fund (17102316) of Research Grants Council, Hong Kong. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.