Marked Decrease in Sleepiness in Patients with Sleep Apnea by Etanercept, a Tumor Necrosis Factor-α Antagonist

Vgontzas, Alexandros N.; Zoumakis, Emmanouil; Lin, Hung Mo; Bixler, Edward O.; Trakada, Georgia; Chrousos, George P.

doi:10.1210/jc.2003-031929

Cited by 310 publications

(186 citation statements)

References 36 publications

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“…In humans, circulating levels of TNFα correlate with sleepiness in health and disease (Dreisbach et al, 1998;Imagawa et al, 2004;Moss et al, 1999;Darko et al, 1995;Obal and Krueger 2003). The soluble TNF receptor reduces fatigue in rheumatoid arthritis patients (Franklin et al, 1999) and in sleep apnea patients reduces sleepiness (Vgontzas et al, 2004). Collectively, such data implicate TNFα in sleep regulation and other brain processes.…”

Section: Discussionmentioning

confidence: 85%

TNFα siRNA reduces brain TNF and EEG delta wave activity in rats

et al. 2007

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Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with several CNS physiological and pathophysiological actions including sleep, memory, thermal and appetite regulation. Short interfering RNAs (siRNA) targeting TNFα were incubated with cortical cell cultures and microinjected into the primary somatosensory cortex (SSctx) of rats. The TNFα siRNA treatment specifically reduced TNFα mRNA by 45% in vitro without affecting interleukin-6 or gluR1-4 mRNA levels. In vivo the TNFα siRNAα reduced TNFα mRNA, interleukin-6 mRNA and gluR1 mRNA levels compared to treatment with a scrambled control siRNA. After in vivo microinjection, the density of TNFα-immunoreactive cells in layer V of the SSctx was also reduced. Electroencephalogram (EEG) delta wave power was decreased on days 2 and 3 on the side of the brain that received the TNFα siRNA microinjection relative to the side receiving the control siRNA. These findings support the hypothesis that TNFα siRNA attenuates TNFα mRNA and TNFα protein in the rat cortex and that those reductions reduce cortical EEG delta power. Results also are consistent with the notion that TNFα is involved in CNS physiology including sleep regulation.

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Section: Discussionmentioning

confidence: 85%

TNFα siRNA reduces brain TNF and EEG delta wave activity in rats

et al. 2007

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“…Their somnogenic activity (149)(150)(151)(152)(153) may lead to a global depression on CNS activity and upper airway neuromuscular control. As disturbances in upper airway neuromotor control ensue, increases in sleep apnea severity (154) can trigger further elevations in proinflammatory cytokines and exacerbate sleep apnea (147,148,(155)(156)(157)(158)(159)(160).…”

Section: Putative Adipokine Modulators Of Upper Airway Functionmentioning

confidence: 99%

Obesity and Obstructive Sleep Apnea: Pathogenic Mechanisms and Therapeutic Approaches

Schwartz

Patil²,

Laffan

et al. 2008

Proceedings of the American Thoracic Society

584

395

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Obstructive sleep apnea is a common disorder whose prevalence is linked to an epidemic of obesity in Western society. Sleep apnea is due to recurrent episodes of upper airway obstruction during sleep that are caused by elevations in upper airway collapsibility during sleep. Collapsibility can be increased by underlying anatomic alterations and/or disturbances in upper airway neuromuscular control, both of which play key roles in the pathogenesis of obstructive sleep apnea. Obesity and particularly central adiposity are potent risk factors for sleep apnea. They can increase pharyngeal collapsibility through mechanical effects on pharyngeal soft tissues and lung volume, and through central nervous system-acting signaling proteins (adipokines) that may affect airway neuromuscular control. Specific molecular signaling pathways encode differences in the distribution and metabolic activity of adipose tissue. These differences can produce alterations in the mechanical and neural control of upper airway collapsibility, which determine sleep apnea susceptibility. Although weight loss reduces upper airway collapsibility during sleep, it is not known whether its effects are mediated primarily by improvement in upper airway mechanical properties or neuromuscular control. A variety of behavioral, pharmacologic, and surgical approaches to weight loss may be of benefit to patients with sleep apnea, through distinct effects on the mass and activity of regional adipose stores. Examining responses to specific weight loss strategies will provide critical insight into mechanisms linking obesity and sleep apnea, and will help to elucidate the humoral and molecular predictors of weight loss responses.

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“…48 Clinically available inhibitors of IL1 or TNF reduce the sleepiness and fatigue associated with rheumatoid arthritis 49 and sleep apnea. 50 Furthermore, surgical treatment of obstructive sleep apnea reduces plasma levels of TNF as well as sleepiness. 51 The link between pathology, cytokine levels, and sleep suggest that some primary sleep disorders such as sleep apnea or insomnia are chronic inflammatory disorders.…”

Section: Atp-cytokine-adenosine Hypothesismentioning

confidence: 99%