Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase-dependent Pathways in Mouse

• Published in: American journal of respiratory and critical care medicine 2011-12, Vol.184 (11), p.1305-1312
• Main Authors: NAIR, Deepti, ZHANG, Shelley X. L, RAMESH, Vijay, HAKIM, Fahed, KAUSHAL, Navita, YANG WANG, GOZAL, David
• Format: Article
• Language: English
• Subjects: Adenosine; Analysis of Variance; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Behavior, Animal; Biological and medical sciences; Blood coagulation. Blood cells; Cognition Disorders - etiology; Cognition Disorders - metabolism; Cognitive ability; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; General aspects, investigation methods, hemostasis, fibrinolysis; Hypoxia; Intensive care medicine; Kinases; Lipid Peroxidation; Male; Maze Learning; Medical sciences; Memory; Mice; Mice, Transgenic; Molecular and cellular biology; NADPH Oxidases - metabolism; Oxidative Stress; Paradigms; Protons; Sleep apnea; Sleep deprivation; Sleep Deprivation - complications; Sleep Deprivation - metabolism; Swimming
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201107-1173OC

Sleep fragmentation (SF) is one of the major characteristics of sleep apnea, and has been implicated in its morbid consequences, which encompass excessive daytime sleepiness and neurocognitive impairments. We hypothesized that absence of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is neuroprotective in SF-induced cognitive impairments. To examine whether increased NADPH oxidase activity may play a role in SF-induced central nervous system dysfunction. The effect of chronic SF during the sleep-predominant period on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters was assessed in mice lacking NADPH oxidase activity (gp91phox-(/Y)) and wild-type littermates. SF for 15 days was not associated with differences in sleep duration, sleep state distribution, or sleep latency in both gp91phox-(/Y) and control mice. However, on a standard place training task, gp91phox-(/Y) mice displayed normal learning and were protected from the spatial learning deficits observed in wild-type littermates exposed to SF. Moreover, anxiety levels were increased in wild-type mice exposed to SF, whereas no changes emerged in gp91phox-(/Y) mice. Additionally, wild-type mice, but not gp91phox-(/Y) mice, had significantly elevated NADPH oxidase gene expression and activity, and in malondialdehyde and 8-oxo-2'-deoxyguanosine levels in cortical and hippocampal lysates after SF exposures. This work substantiates an important role for NADPH oxidase in hippocampal memory impairments induced by SF, modeling sleep apnea. Targeting NADPH oxidase, therefore, is expected to minimize hippocampal impairments from both intermittent hypoxia and SF associated with the disease.