Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea

PLoS One. 2011;6(5):e19847. doi: 10.1371/journal.pone.0019847. Epub 2011 May 23.


Background: In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction.

Methods and findings: The effect of IH during light period on two forms of spatial learning in the water maze and well as markers of oxidative stress was assessed in mice lacking NADPH oxidase activity (gp91phox(_/Y)) and wild-type littermates. On a standard place training task, gp91phox(_/Y) displayed normal learning, and were protected from the spatial learning deficits observed in wild-type littermates exposed to IH. Moreover, anxiety levels were increased in wild-type mice exposed to IH as compared to room air (RA) controls, while no changes emerged in gp91phox(_/Y) mice. Additionally, wild-type mice, but not gp91phox(_/Y) mice had significantly elevated levels of NADPH oxidase expression and activity, as well as MDA and 8-OHDG in cortical and hippocampal lysates following IH exposures.

Conclusions: The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and thus pharmacological agents targeting NADPH oxidase may provide a therapeutic strategy in sleep-disordered breathing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Animals
  • Cognition Disorders / etiology*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Disease Models, Animal*
  • Hypoxia / physiopathology*
  • Lipid Peroxidation
  • Male
  • Maze Learning
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidase 2
  • NADPH Oxidases / physiology*
  • Sleep Apnea Syndromes / complications*
  • Sleep Apnea Syndromes / enzymology
  • Swimming


  • Membrane Glycoproteins
  • 8-Hydroxy-2'-Deoxyguanosine
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Deoxyguanosine