A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

Abstract

Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and increased blood-brain barrier permeability.

Chronic sleep restriction disrupts interendothelial junctions in the hippocampus and increases blood–brain barrier permeability

“…Similar to the findings reported here, Hurtado‐Alvarado et al . () found that 10‐day sleep restriction decreased tight junction protein expression in the hippocampus, and the effect was rapidly reverted by the administration of a selective antagonist of A 2A adenosine receptors. Likely, He et al .…”

“…Previous reports showed that chronic sleep restriction increased blood–brain barrier permeability to large molecules such as Evans blue, 10 kDa and 70 kDa FITC‐dextrans (Gómez‐González et al ., ; Hurtado‐Alvarado et al ., ) as well as small molecules such as fluorescein‐Na (He et al ., ). Particularly, the hippocampus showed a slow reduction in the permeability to Evans blue along the time of sleep recovery in the 10th day of sleep restriction; however, permeability remained higher than the control group even after 120 min of sleep recovery (Gómez‐González et al ., ).…”

“…() found that sleep restricted animals presented increased plasma levels of C‐reactive protein and increased mRNA expression of COX‐2 in the brain, as well as the report by Hurtado‐Alvarado et al . () showing that A 2A adenosine receptor antagonism reverted the blood–brain barrier hyper‐permeability and the tight junction protein changes induced by chronic sleep loss, point to a role of inflammatory mediators in regulating blood–brain barrier permeability during sleep loss as previously hypothesised by Hurtado‐Alvarado et al . ().…”

Traumatic Stress and Accelerated Cellular Aging: From Epigenetics to Cardiometabolic Disease

“…Related to this, given that BBB degradation may result, in part, from substantial peripheral inflammation related to both PTSD and metabolic pathologies [103, 104], intriguing targets for intervention include pharmacological agents involved in BBB integrity. For example, adenosine has been shown to enhance gliosis, inflammation, and BBB permeability secondary to sleep loss [105, 106]. Research in rodent models has shown that antagonism of the adenosine receptor A 2A is able to reverse sleep-restriction induced increases in BBB permeability [105], suggesting another potential approach for reversing accelerated aging.…”

“…For example, adenosine has been shown to enhance gliosis, inflammation, and BBB permeability secondary to sleep loss [105, 106]. Research in rodent models has shown that antagonism of the adenosine receptor A 2A is able to reverse sleep-restriction induced increases in BBB permeability [105], suggesting another potential approach for reversing accelerated aging.…”