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Inducible Nitric Oxide Synthase in Long-term Intermittent Hypoxia

Hypersomnolence and Brain Injury

Center for Sleep and Respiratory Neurobiology, Department of Medicine, and Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Sigrid C. Veasey, M.D., 987 Maloney Building, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104. E-mail: veasey{at}mail.med.upenn.edu

Rationale: 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. Objectives: 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. Measurements and Main 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 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.

Key Words: basal forebrain • carbonylation • chronic intermittent hypoxia • locus coeruleus • oxidative

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