Finding the Cause of Residual Sleeplessness in Sleep Apnea
Obstructive sleep apnea (OSA) with daytime sleepiness, hypersomnolence and fatigue is present in at least 12 million adults in the United States. Two thirds of adults with OSA complain of significant sleepiness, which correlates with severity of cognitive impairment in these individuals. When treated for OSA, patients typically report marked improvement in sleepiness and fatigue. However, randomized controlled trials measuring sleepiness with the multiple sleep latency test show that many individuals with sleep apnea still have significant sleepiness despite successful treatment.
The observation of persistent sleepiness in patients despite proper CPAP pressures, full patient compliance and the exclusion of other sleep disorders, prompted Dr. Sigrid Veasey and co-workers in Penn's Center for Sleep and Respiratory Neurobiology to ask a novel clinical question: what physiological perturbance in OSA best predicts residual sleepiness?
Based on the observation that oxygen desaturation correlates best with sleepiness, rather than sleep time, apnea/hypopnea index or arousal index, Dr. Veasey decided to use a murine model to examine the effect of long-term intermittent hypoxia on sleep and sleepiness.
She found that long-term intermittent hypoxia in mice results in marked reductions in wake time persisting at least several weeks after normal oxygenation is restored. In addition, average sleep latency and duration of wakefulness are significantly shortened. This persistence in impaired wakefulness following long-term intermittent hypoxia prompted Dr. Veasey to ask whether neurons in wake-active regions might be vulnerable to lasting oxidative injury from long-term intermittent hypoxia.
Long-term intermittent hypoxia increases nitration and oxidation in many brain regions including those involved in sleep/wake control. A major source of longterm intermittent hypoxia -induced nitration appears to be inducible nitric oxide synthase (iNOS): Mice with transgenic absence of functional iNOS have less impaired wakefulness following long-term intermittent hypoxia and less nitration injury in wake active regions. In wild type mice, acute inhibition of iNOS following long-term intermittent hypoxia reduces the proinflammatory response, but oxidation injury persists. Thus, irreversible oxidative injury to wake areas occurs from the hypoxia/reoxygenation events of sleep apnea.
Hypothesizing that the major source of superoxide
radicals producing oxidative injury in long-term
intermittent hypoxia is NAD(P)H oxidase, Dr.
Veasey studied the effects of transgenic absence
of functional NADPH oxidase and pharmacological
inhibition of NADPH oxidase during long-term
intermittent hypoxia in mice. She found that
both transgenic absence and pharmacological inhibition
conferred complete resistance to impaired wakefulness,
oxidation, the proinflammatory response, and
nitration.
Thus, NADPH oxidase appears to be at
the gateway for most long-term intermittent hypoxic
injuries. This provides an enzyme to target for
the prevention of residual sleepiness in sleep
apnea. Future studies will further elucidate
this pathway, but the findings are promising
enough to begin design of clinical trials for
adults with obstructive sleep apnea.
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