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.
Highlights
Long-term insufficient sleep has adverse effects on overall health and impairments in cognition [1, 2]
Sleep restriction increased blood-brain barrier permeability to 10-kDa Fluorescein isothiocyanate (FITC)-dextran and adenosine receptor antagonism reverted the effect of sleep restriction in almost all brain regions studied (Group effect, F5 = 16.756, p
Sleep restriction increased blood-brain barrier permeability to FITC-dextran and Evans blue; the changes in blood-brain barrier permeability were observed for both low- and high-molecular weight tracers in the cortex, hippocampus, basal nuclei and cerebellar vermis of sleep-restricted rats as compared to controls sleeping ad libitum
Summary
Long-term insufficient sleep has adverse effects on overall health and impairments in cognition [1, 2]. Cognitive deficits during sleep loss may be related to alterations in the interface between the periphery and the central nervous system, the blood-brain barrier. This barrier restricts the entry of toxic blood-borne molecules into the brain. In this way, chronic sleep restriction induces blood-brain barrier hyperpermeability to Evans blue and sodium fluorescein, increases pinocytosis, and decreases mRNA expression of tight junction proteins in rodents [3, 4]. After brief sleep opportunity periods of 40 and 120 minutes, the blood-brain barrier permeability to Evans blue in almost all brain regions decreases to basal levels excluding cerebellar vermis [3]. Adenosine concentration in the basal forebrain, hippocampus and cortex increases progressively with prolonged waking [7] or during sleep deprivation, and decreases during sleep [8]
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