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

Deepti Nair,David Gozal,Shelley X Zhang,Yang Wang,Ehab A Dayyat,Ya-Ping Tang

doi:10.1371/journal.pone.0019847

Abstract

BackgroundIn 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.Methods and FindingsThe 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.ConclusionsThe 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.

Highlights

Obstructive Sleep Apnea (OSA), a clinical syndrome characterized by repeated episodes of upper airway obstruction during sleep, is recognized as a significant and highly prevalent health problem, due to its cardiovascular and metabolic morbidity, and because of the prominent cognitive and behavioral implications of the disease
The oxidative stress responses and neurobehavioral impairments induced by intermittent hypoxia (IH) during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and pharmacological agents targeting NADPH oxidase may provide a therapeutic strategy in sleep-disordered breathing
The inordinate sensitivity of neuronal tissues to alterations in oxygen homeostasis has led to the hypothesis that the behavioral consequences and cellular losses observed in obstructive sleep apnea (OSA) patients are produced, at least in part, by the episodic hypoxia-reoxygenation cycles during sleep that characterize OSA

Summary

Introduction

Obstructive Sleep Apnea (OSA), a clinical syndrome characterized by repeated episodes of upper airway obstruction during sleep, is recognized as a significant and highly prevalent health problem, due to its cardiovascular and metabolic morbidity, and because of the prominent cognitive and behavioral implications of the disease. The inordinate sensitivity of neuronal tissues to alterations in oxygen homeostasis has led to the hypothesis that the behavioral consequences and cellular losses observed in OSA patients are produced, at least in part, by the episodic hypoxia-reoxygenation cycles during sleep that characterize OSA In support of this hypothesis, rodent models have demonstrated that chronic exposure to intermittent hypoxia during the rest period (IH), in the absence of significant sleep fragmentation, is accompanied by neurodegenerative changes, increased oxidant stress and inflammation, and impaired spatial learning in the Morris water maze [6,7,8,9,10,11,12,13,14,15,16,17,18], and that genetic or pharmacological manipulations of oxidative stress pathways attenuated IH-induced deficits [18,19]. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction

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