Long-term intermittent hypoxia in mice: Protracted hypersomnolence with oxidative injury to sleep-wake brain regions

Sigrid Carlen Veasey, Christine W. Davis, Polina Fenik, Guanxia Zhan, Yeou Jey Hsu, Domenico Pratico, Andrew Gow

Research output: Contribution to journalArticlepeer-review

281 Scopus citations


Study Objectives: This study was designed to test the hypothesis that long-term intermittent hypoxia (LTIH), modeling the hypoxia-reoxygenation events of sleep apnea, results in oxidative neural injury, including wake-promoting neural groups, and that this injury contributes to residual impaired maintenance of wakefulness. Design: Sleep times and oxidative-injury parameters were compared for mice exposed to LTIH and mice exposed to sham LTIH. Subjects: Adult male C57BL/6J mice were studied. Interventions: Mice were exposed to LTIH or sham LTIH in the lights-on period daily for 8 weeks. Electrophysiologic sleep-wake recordings and oxidative-injury measures were performed either immediately or 2 weeks following LTIH exposures. Measurements and Results: At both intervals, total sleep time per 24 hours in LTIH-exposed mice was increased by more than 2 hours, (P<.01). Mean sleep latency was reduced in LTIH-exposed mice relative to sham LTIH mice (8.9 ± 1.0 minutes vs 12.7 ± 0.5 minutes, respectively, P<.01). Oxidative injury was present 2 weeks following LTIH in wake-promoting regions of the basal forebrain and brainstem: elevated isoprostane 8,12-iso-IPF-VI, 22%, P<.05; increased protein carbonylation, 50%, P<.05, increased nitration, 200%, P<05, and induction of antioxidant enzymes glutathione reductase and methionine sulfoxide reductase A, P<.01. Conclusions: Exposure to LTIH results in an array of significant oxidative injuries in sleep-wake regions of the brain, and these biochemical changes are associated with marked hypersomnolence and increased susceptibility to short-term sleep loss. The residual forebrain redox alterations in wake-promoting brain regions may contribute to persistent sleepiness in a prevalent disorder, obstructive sleep apnea.

Original languageEnglish (US)
Pages (from-to)194-201
Number of pages8
Issue number2
StatePublished - 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Physiology (medical)


  • Apnea
  • Hypoxia
  • Oxidation
  • Oxidative stress
  • Wakefulness


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