Sera of elderly obstructive sleep apnea patients alter blood–brain barrier integrity in vitro: a pilot study

Abstract

Obstructive sleep apnea syndrome (OSAS) is characterized by repeated episodes of hypoxia during the night. The severity of the disorder can be evaluated using an apnea–hypopnea index (AHI). The physiological consequences are mainly cardiovascular and neuronal dysfunctions. One hypothesis to explain such associated neurological disorders is disruption of the blood–brain barrier (BBB), which protects the brain from endovascular cytotoxic compounds. We selected two subgroups of volunteers from the PROOF cohort study (France), a group of patients suffering newly diagnosed severe OSAS (AHI > 30/h) and a group showing no sleep apnea (AHI < 5/h). We exposed a human in vitro BBB model of endothelial cells (HBEC-5i) with sera of patients with and without OSAS. After exposure, we measured the apparent BBB permeability as well as tight junction and ABC transporter expression using whole cell ELISA. We showed that after incubation with sera from OSAS patients, there was a loss of integrity in the human in vitro BBB model; this was reflected by an increase in permeability (43%; p < 0.001) and correlated with a 50% and 40% decrease in tight junction protein expression of ZO-1 and claudin-5, respectively. At the same time, we observed an upregulation in Pgp protein expression (52%) and functionality, and a downregulation in BCRP expression (52%). Our results demonstrated that severe BBB disorder after exposure to sera from OSAS patients was reflected by an opening of the BBB.

Obstructive Sleep Apnea, Hypercoagulability, and the Blood–Brain Barrier

“…A recent review and other studies have shown that the blood–brain barrier (BBB) could be altered by several mechanisms that are present during OSA [ 78 , 79 , 80 ]. The BBB secludes the brain from the undesired transfer of substances that may be in the bloodstream while allowing the passage of nutrients that are essential for brain function.…”

Brain Mechanisms of COVID-19-Sleep Disorders

“…However, there is emerging evidence that the major complication of sleep loss is neuroinflammation, which induces BBB disruption (Table 1). Indeed, sleep loss per se, including sleep deprivation, sleep restriction, sleep fragmentation, or sleep apnea in human and rodents induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them can promote changes in cellular components of the BBB, particularly on brain endothelial cells [35][36][37][38][39][40][41][42][43][44][45][46]. In this session, we discuss the role of inflammatory mediators that increase during sleep loss and how these changes may alter the BBB permeability as well as we analyze hypothetical mechanisms by which sleep deprivation may induce the BBB disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.…”

“…Recently, it has been discovered that sleep deprivation increases the BBB permeability to inflammatory mediators, immune cells, and exogenous tracers in humans and rodents [35,36,38,39,[41][42][43]45,50,[54][55][56]. Chronic sleep restriction diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of BBB and decreased 2-deoxy-glucose uptake by the brain.…”

“…Sleep disturbances also increase the BBB permeability in humans [41][42][43]45]. Indeed, acute sleep deprivation induces an increase in the serum levels of neuron-specific enolase and S100 calcium-binding protein B (S-100B) in healthy young men [45].…”

“…That in turn, decreases nitric oxide and enhances endothelin, amyloid-β deposition, cerebral amyloid angiopathy, and BBB disruption [42]. Voirin A.C. et al used the human in vitro BBB model of endothelial cells (HBEC-5i) with sera of patients with and without obstructive sleep apnea [43]. They demonstrated that obstructive sleep apnea is accompanied by BBB disruption and a decrease in tight junction protein expression of zonula occludes-1 and claudin-5.…”