NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea

Am J Respir Crit Care Med. 2005 Oct 1;172(7):921-9. doi: 10.1164/rccm.200504-581OC. Epub 2005 Jun 30.


Rationale: Persons with obstructive sleep apnea may have significant residual hypersomnolence, despite therapy. Long-term hypoxia/reoxygenation events in adult mice, simulating oxygenation patterns of moderate-severe sleep apnea, result in lasting hypersomnolence, oxidative injury, and proinflammatory responses in wake-active brain regions. We hypothesized that long-term intermittent hypoxia activates brain NADPH oxidase and that this enzyme serves as a critical source of superoxide in the oxidation injury and in hypersomnolence.

Objectives: We sought to determine whether long-term hypoxia/reoxygenation events in mice result in NADPH oxidase activation and whether NADPH oxidase is essential for the proinflammatory response and hypersomnolence.

Methods: NADPH oxidase gene and protein responses were measured in wake-active brain regions in wild-type mice exposed to long-term hypoxia/reoxygenation. Sleep and oxidative and proinflammatory responses were measured in adult mice either devoid of NADPH oxidase activity (gp91phox-null mice) or in which NADPH oxidase activity was systemically inhibited with apocynin osmotic pumps throughout hypoxia/reoxygenation.

Main results: Long-term intermittent hypoxia increased NADPH oxidase gene and protein responses in wake-active brain regions. Both transgenic absence and pharmacologic inhibition of NADPH oxidase activity throughout long-term hypoxia/reoxygenation conferred resistance to not only long-term hypoxia/reoxygenation hypersomnolence but also to carbonylation, lipid peroxidation injury, and the proinflammatory response, including inducible nitric oxide synthase activity in wake-active brain regions.

Conclusions: Collectively, these findings strongly support a critical role for NADPH oxidase in the lasting hypersomnolence and oxidative and proinflammatory responses after hypoxia/reoxygenation patterns simulating severe obstructive sleep apnea oxygenation, highlighting the potential of inhibiting NADPH oxidase to prevent oxidation-mediated morbidities in obstructive sleep apnea.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disorders of Excessive Somnolence / physiopathology*
  • Gene Expression
  • Hypoxia / physiopathology*
  • Immunohistochemistry
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidase 2
  • NADPH Oxidases / physiology*
  • Oxidative Stress
  • Prosencephalon / metabolism


  • Membrane Glycoproteins
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases