Review
Reactive oxygen species and the brain in sleep apnea

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Abstract

Rodents exposed to intermittent hypoxia (IH), a model of obstructive sleep apnea (OSA), manifest impaired learning and memory and somnolence. Increased levels of reactive oxygen species (ROS), oxidative tissue damage, and apoptotic neuronal cell death are associated with the presence of IH-induced CNS dysfunction. Furthermore, treatment with antioxidants or overexpression of antioxidant enzymes is neuroprotective during IH. These findings mimic clinical cases of OSA and suggest that ROS may play a key causal role in OSA-induced neuropathology. Controlled production of ROS occurs in multiple subcellular compartments of normal cells and de-regulation of such processes may result in excessive ROS production. The mitochondrial electron transport chain, especially complexes I and III, and the NADPH oxidase in the cellular membrane are the two main sources of ROS in brain cells, although other systems, including xanthine oxidase, phospholipase A2, lipoxygenase, cyclooxygenase, and cytochrome P450, may all play a role. The initial evidence for NADPH oxidase and mitochondrial involvement in IH-induced ROS production and neuronal injury unquestionably warrants future research efforts.

Introduction

Reactive oxygen species (ROS) can be generated from various subcellular compartments, including mitochondria, the cellular membrane, lysosomes, peroxisomes, and the endoplasmic reticulum (Angermuller et al., 2009, Bedard and Krause, 2007, Droge, 2002, Kubota et al., 2010, Santos et al., 2009). While ROS production in mitochondria relies solely on the electron transport chain, it usually involves multiple enzymatic systems in other subcellular compartments. For example, NADPH oxidase (Akki et al., 2009, Bedard and Krause, 2007), xanthine oxidase (Berry and Hare, 2004), phospholipase A2 (Muralikrishna Adibhatla and Hatcher, 2006), lipoxygenases and cyclooxygenase (Droge, 2002), and cytochrome P450 (Yasui et al., 2005) have all been identified as sources of ROS in various subcellular compartments under both physiological and pathological conditions (Fig. 1). However, since mitochondria and NADPH oxidase are arguably the predominant sources of ROS in the central nervous system and have been more recently shown to play a role in intermittent hypoxia-induced neuronal deficits, the current review will focus on these two systems and their interactions. Involvement of other ROS-producing systems in sleep apnea-related neuropathology has not been thus far either explored or confirmed. However, such involvement should not be excluded and definitely warrants additional future investigation.

Section snippets

Mitochondria

Mitochondria are the major cellular source of reactive oxygen species (ROS) in most non-phagocytic cells under normal conditions. As the cellular power plant, mitochondria convert energy contained in nutrients to ATP, the universal energy currency of all biological systems, through oxidative phosphorylation. During this process, a pair of electrons is donated by NADH to complex I (NADH-ubiquinone oxidoreductase) or by FADH2 to complex II (succinate dehydrogenase) of the electron transport chain

NADPH oxidase

NADPH oxidase is a multi-subunit enzyme complex, localized in both the plasma membrane and membranes of subcellular organelles, that catalyzes electron transfer from NADPH to molecular oxygen, producing superoxide. NADPH oxidase was first identified in phagocytes where its ROS-producing function plays an essential role in non-specific host defense against microbes during phagocytosis (Lambeth, 2004). It was soon found that enzyme systems similar to the phagocyte NADPH oxidase existed in many

Cross-talk between mitochondria and the NADPH oxidase

While mitochondria and the NADPH oxidase are each capable of producing superoxide independently, emerging evidence suggests the existence of a cross-talk between the two cellular systems in which they appear to be co-stimulatory (Daiber, 2010). Several studies have shown that mitochondria may regulate superoxide production by NADPH oxidase. For example, increased NADPH oxidase activity and superoxide production induced by hypoxia or serum withdrawal were diminished by inhibition of

The clinical spectrum of SBD and OSAS

Before we address the main question, it seems appropriate to provide a quick overview of the clinical term of sleep-disordered breathing (SDB). Indeed, SDB encompasses a spectrum of respiratory disturbances during sleep, ranging from intermittent snoring to obstructive sleep apnea syndrome (OSAS). OSAS, the most severe form of SBD, affects approximately 3–5% of the general population including children, and is characterized by repeated episodes of upper airway obstruction during sleep (Lumeng

Summary

The cumulative evidence is supportive for ROS playing a major role in the deleterious effects of IH on selected CNS structures. The putative mechanisms underlying neuronal dysfunction and loss as well as reactive gliosis in animals and humans exposed to IH during sleep remain however poorly defined. Recent findings implicating NADPH oxidase and mitochondrial dysfunction as important sources of excessive ROS production in the context of IH provide a well needed impetus for accurate delineation

Conflict of interest

The authors have no conflict of interest to declare in relation to this manuscript.

Acknowledgements

DG is supported by National Institutes of Health grants HL65270 and HL086662.

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