© 2005 American Thoracic Society doi: 10.1164/rccm.2503004
Sleepiness and Neurodegeneration in Sleep-disordered BreathingConvergence of Signaling CascadesDivision of Pediatric Sleep Medicine, Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, Kentucky Sleep-disordered breathing (SDB), a clinical syndrome characterized by repeated episodes of upper airway obstruction during sleep that manifest as intermittent hypoxemia and hypercapnia, with periodic arousals, is now recognized as a significant and highly prevalent public health problem that imposes substantial cardiovascular and neurocognitive morbidities in all age groups (1, 2). Neuropsychologic impairments are consistently observed in patients suffering from SDB, and increased systemic markers of oxidative stress and inflammation have been reported in patients with SDB (3, 4). Furthermore, gray matter loss within brain regions known for their role in cognitive function has also been found (5, 6), suggesting that alterations in oxygen homeostasis during sleep lead to neural cell losses and consequent neurobehavioral morbidities in patients with SDB. In addition to the neurocognitive functional disturbances associated with SDB, impaired vigilance and increased sleep propensity are commonly seen in these patients, and will not always resolve despite institution of adequate therapy (7, 8). The partial responsiveness to SDB-directed treatment suggests that loss of neuronal substrates in selective brain regions may underlie such residual deficits. As such, improved understanding of the mechanisms mediating regional brain cellular losses is of critical importance for development of improved therapies for these patients. WHAT DO WE KNOW THUS FAR? A rodent model of SDB, consisting of the application of intermittent hypoxia during the circadian period associated with sleep, reveals that selective neuronal cell losses occur in brain regions mediating cognitive function and sleep–wake regulation (9, 10). Furthermore, induction of cellular apoptotic events associated with intermittent hypoxia involves activation of several proinflammatory pathways, particularly those that include biologically active phospholipids, such as platelet-activating factor, excitotoxic release of glutamate, excessive formation of oxidation products, induction of cyclooxygenase 2, release of proinflammatory cytokines, and downstream alteration of signaling pathways with recognized roles in cell survival and memory functions (Figure 1) (11–14).
In this issue of the Journal (pp. 1414–1420), Zhan and colleagues provide conclusive evidence that enhanced expression and function of the inducible form of nitric oxide synthase (iNOS) is also an important contributor to the oxidative and inflammatory injury induced by intermittent hypoxia to wake-promoting regions of the brain, such as the laterobasal forebrain and posterolateral hypothalamus (15). Indeed, either pharmacologic inhibition of iNOS or genetic ablation of the enzyme in mice was associated with markedly reduced protein oxidative injury and cyclooxygenase expression as well as reciprocal decreases in sleepiness. Thus, increased iNOS activity induced by episodic hypoxia during sleep may not only play a role in the pathophysiologic mechanisms associated with neuronal cell losses in wake-regulatory regions, through increased formation of reactive nitrogen species and subsequent cellular injury, but could also provide a chemical signaling pathway for increased neuronal activation of sleep-promoting brain regions. These findings involving specific brain regions regulating sleep functions are uniquely reminiscent of the role played by iNOS in other brain regions involved in cognitive and memory functions (16). These results therefore suggest that iNOS induction by intermittent hypoxia during sleep operates as a global effector of cellular injury within vulnerable brain regions. Furthermore, the studies from Zhan and colleagues reveal that the episodic nature of hypoxia, rather than hypoxia per se, is associated with the upregulation of iNOS expression and activity, and is likely to contribute to its deleterious consequences. WHERE SHOULD WE GO FROM HERE? The unique similarity among the pathogenetic mechanisms involved in neurodegenerative diseases, such as Alzheimer's disease, Parkinson disease, and SDB-associated neurodegenerative changes, should prompt us to view SDB as an inflammatory brain disorder and explore the potential value of pharmacologic interventions currently used in the management of such disorders. Obviously first and foremost among candidate drugs to be tested, the efficacy of iNOS blockers in preventing cognitive losses and ameliorating excessive sleepiness in patients with SDBs should be examined. After all, iNOS should stand as a mnemonic for our aims to achieve "I NO Sleepy" states among all patients with SDB. FOOTNOTES Conflict of Interest Statement: D.G. is a speaker for Merck Company and is the recipient of a research grant from AstraZeneca; L.K. does not have a financial relationship with a commercial entity that has an interest in the subject of the manuscript. REFERENCES
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