Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea

• Published in: PloS one 2011-05, Vol.6 (5), p.e19847-e19847
• Main Authors: Nair, Deepti, Dayyat, Ehab A, Zhang, Shelley X, Wang, Yang, Gozal, David
• Format: Article
• Language: English
• Subjects: 8-Hydroxydeoxyguanosine; Airway management; Animal cognition; Animal models; Animals; Anxiety; Apnea; Apoptosis; Biology; Brain; Breathing; Central nervous system; Cognition Disorders - etiology; Cognitive ability; Cortex; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Disease Models, Animal; Experiments; Exposure; Hippocampus; Hypotheses; Hypoxia; Hypoxia - physiopathology; Light; Light effects; Lipid Peroxidation; Lysates; Male; Maze Learning; Medicine; Membrane Glycoproteins - physiology; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; NAD(P)H oxidase; NADPH Oxidase 2; NADPH Oxidases - physiology; Observational learning; Oxidase; Oxidases; Oxidative stress; Oxidizing agents; Pediatrics; Pharmacology; Polyphenols; Rodents; Signal transduction; Sleep; Sleep apnea; Sleep Apnea Syndromes - complications; Sleep Apnea Syndromes - enzymology; Sleep disorders; Spatial discrimination learning; Swimming
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019847

In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction. The effect of IH during light period on two forms of spatial learning in the water maze and well as markers of oxidative stress was assessed in mice lacking NADPH oxidase activity (gp91phox(_/Y)) and wild-type littermates. On a standard place training task, gp91phox(_/Y) displayed normal learning, and were protected from the spatial learning deficits observed in wild-type littermates exposed to IH. Moreover, anxiety levels were increased in wild-type mice exposed to IH as compared to room air (RA) controls, while no changes emerged in gp91phox(_/Y) mice. Additionally, wild-type mice, but not gp91phox(_/Y) mice had significantly elevated levels of NADPH oxidase expression and activity, as well as MDA and 8-OHDG in cortical and hippocampal lysates following IH exposures. The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and thus pharmacological agents targeting NADPH oxidase may provide a therapeutic strategy in sleep-disordered breathing.