Inducible nitric oxide synthase in long-term intermittent hypoxia: hypersomnolence and brain injury.
BACKGROUND
Long-term intermittent hypoxia (LTIH) exposure in adult mice, modeling oxygenation patterns of moderate-severe obstructive sleep apnea, results in lasting hypersomnolence and is associated with nitration and oxidation injuries in many brain regions, including wake-active regions.


OBJECTIVE
We sought to determine if LTIH activates inducible nitric oxide synthase (iNOS) in sleep/wake regions, and if this source of NO contributes to the LTIH-induced proinflammatory gene response, oxidative injury, and wake impairments.


METHODS
Mice with genetic absence of iNOS activity and wild-type control animals were exposed to 6 weeks of long-term hypoxia/reoxygenation before behavioral state recordings, molecular and biochemical assays, and a pharmacologic intervention.


RESULTS
Two weeks after recovery from hypoxia/reoxygenation exposures, wild-type mice showed increased iNOS activity in representative wake-active regions, increased sleep times, and shortened sleep latencies. Mutant mice, with higher baseline sleep times, showed no effect of long-term hypoxia/reoxygenation on sleep time latencies and were resistant to hypoxia/reoxygenation increases in lipid peroxidation and proinflammatory gene responses (tumor necrosis factor alpha and cyclooxygenase 2). Inhibition of iNOS after long-term hypoxia/reoxygenation in wild-type mice was effective in reversing the proinflammatory gene response.


CONCLUSIONS
These data support a critical role for iNOS activity in the development of LTIH wake impairments, lipid peroxidation, and proinflammatory responses in wake-active brain regions, and suggest a potential role for inducible NO inhibition in protection from proinflammatory responses, oxidative injury, and residual hypersomnolence in obstructive sleep apnea.
Zhan
Guanxia
G
Center for Sleep and Respiratory Neurobiology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Fenik
Polina
P
Pratico
Domenico
D
Veasey
Sigrid C
SC
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D006970:Disorders of Excessive Somnolence / Q000209:etiology* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D002534:Hypoxia, Brain / Q000150:complications / Q000201:enzymology*; D028421:Isoprostanes / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity
D028421:Isoprostanes; D019001:Nitric Oxide Synthase