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


METHODS
Sleep times and oxidative-injury parameters were compared for mice exposed to LTIH and mice exposed to sham LTIH.


METHODS
Adult male C57BL/6J mice were studied.


METHODS
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.


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-IPF2alpha-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.
Veasey
Sigrid C
SC
Center for Sleep & Respiratory Neurobiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. veasey@mail.med.upenn.edu
Davis
Christine W
CW
Fenik
Polina
P
Zhan
Guanxia
G
Hsu
Yeou-Jey
YJ
Pratico
Domenico
D
Gow
Andrew
A
D000818:Animals; D006970:Disorders of Excessive Somnolence / Q000209:etiology*; D004567:Electrodes, Implanted; D002534:Hypoxia, Brain / Q000150:complications* / Q000503:physiopathology*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D016548:Prosencephalon / Q000503:physiopathology; D020178:Sleep Disorders, Circadian Rhythm / Q000503:physiopathology*