Reactive oxygen species and the brain in sleep apnea

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.

Figure 1

An overview of cellular sources of ROS. The electron transport chain (ETC) in the inner mitochondrial membrane (IMM) releases superoxide to both the matrix and the intermembrane space (IMS). NADPH oxidases (NOX) are localized in the cellular and endoplasmic reticulum membranes and release superoxide towards the luminal side of the membranes. Xanthine oxidase (XO) is localized on the outer surface of the cellular membrane, in the cytosol, and in peroxisomes and lysosomes. XO produces both superoxide and H₂O₂. The cytosolic phospholipase A2 (cPLA2) is associated with the lipid layer of the cellular membrane and membranes of subcellular organelles. It releases superoxide to the cytosol. The secretory PLA2 (sPLA2) is localized in the extracellular space where it produces superoxide. Cytochrome P450 is localized in the cellular and endoplasmic reticular membranes and releases superoxide to the cytosol. Cyclooxygenase (COX) and lipoxygenase (LOX) are localized in the endoplasmic reticular membrane and release superoxide into the cytosol. Superoxide is reduced to H₂O₂ by MnSOD in the mitochondrial matrix, by CuZnSOD in the IMS and the cytosol, and by ecSOD in the extracellular space. H₂O₂ freely diffuses across membranes, which is depicted by dotted arrows. OMM: outer mitochondrial membrane.

Figure 2

Mechanisms of superoxide production by the electron transport chain (ETC) in the inner mitochondrial membrane. Electrons (e⁻) are donated by energy substrates to complex I and II, respectively, and are transported to complexes III and then IV, where they are accepted by oxygen, through a 4-electron reduction reaction, forming water. Premature leakage of electrons from the ETC may occur at complex I towards the matrix and at complex III towards both the intermembrane space and the matrix. Such premature electron leakage results in formation of superoxide (O₂^•−) through one-electron reduction of oxygen. Solid red arrows: direction of electron transport; solid blue arrows: direction of reverse electron transport; dotted red arrows: direction of electron leakage; dotted blue arrows: direction of electron leakage through reverse electron transport; dotted black arrows: action of selected ETC inhibitors; thick dotted gray arrows: direction of proton translocation associated with electron transport.

Figure 3

Mechanism of superoxide production by NOX2. The NOX2 enzyme is inactive under resting conditions, in which the cytosolic regulatory subunits are dissociated from the two membrane-bound subunits. Upon stimulation, the “organizer subunit” p47phox moves toward the membrane and docks onto p22phox, which leads to the recruitment of other regulatory subunits and the assembly of an active enzyme. The active NOX2 enzyme accepts electrons (e⁻) donated by NADPH and, in a transmembrane redox reaction, transfers them to the outer side of the membrane, where the electrons are accepted by molecular oxygen, forming superoxide.

Figure 4

Representative tracing of obstructed events in a patient during NREM sleep (A). Examples of oxyhemoglobin trends during sleep in 3 different patients suffering from sleep apnea (B–D), illustrating the presence of IH and the unique patient-to-patient variability in oxygenation patterns associated with the condition.