Obstructive sleep apnea (OSA) is characterized by repeated episodes of intermittent hypoxia (IH) and is recognized as an independent risk factor for vascular diseases that are mediated by a multitude of mechanistic pathophysiological cascades including procoagulant factors. The pro-coagulant state contributes to the development of blood clots and to the increase in the permeability of the blood–brain barrier (BBB). Such alteration of BBB may alter brain function and increase the risk of neurodegenerative diseases. We aim to provide a narrative review of the relationship between the hypercoagulable state, observed in OSA and characterized by increased coagulation factor activity, as well as platelet activation, and the underlying neural dysfunction, as related to disruption of the BBB. We aim to provide a critical overview of the existing evidence about the effect of OSA on the coagulation balance (characterized by increased coagulation factor activity and platelet activation) as on the BBB. Then, we will present the emerging data on the effect of BBB disruption on the risk of underlying neural dysfunction. Finally, we will discuss the potential of OSA therapy on the coagulation balance and the improvement of BBB.

Obstructive sleep apnea (OSA) is characterized by intermittent repeated episodes of hypoxia–reoxygenation. OSA is associated with cerebrovascular consequences. An enhanced blood–brain barrier (BBB) permeability has been proposed as a marker of those disorders. We studied in mice the effects of 1 day and 15 days intermittent hypoxia (IH) exposure on BBB function. We focused on the dorsal part of the hippocampus and attempted to identify the molecular mechanisms by combining in vivo BBB permeability (Evans blue tests) and mRNA expression of several junction proteins (zona occludens (ZO-1,2,3), VE-cadherin, claudins (1,5,12), cingulin) and of aquaporins (1,4,9) on hippocampal brain tissues. After 15 days of IH exposure we observed an increase in BBB permeability, associated with increased mRNA expressions of claudins 1 and 12, aquaporins 1 and 9. IH seemed to increase early for claudin-1 mRNA expression as it doubled with 1 day of exposure and returned near to its base level after 15 days. Claudin-1 overexpression may represent an immediate response to IH exposure. Then, after 15 days of exposure, an increase in functional BBB permeability was associated with enhanced expression of aquaporin. These BBB alterations are possibly associated with a vasogenic oedema that may affect brain functions and accelerate neurodegenerative processes.

The main cause of the multidrug resistance (MDR) of glioma cells is the overexpression of MRP-1, often associated with high levels of glutathione (GSH). We investigated whether MRP-1-related GSH content can influence (99m)Tc-glucarate entry by comparing its uptake with that of (99m)Tc-sestamibi (MIBI), an MRP- 1 probe, in an in vitro model of a sensitive cell line (U-87-MG) and a resistant derived cell line expressing MRP-1 (U-87-MG-R). Drug resistance was assessed by immunoblotting, GSH measurement, and Alamar Blue assay. To correlate MDR phenotype with tracer accumulation, uptakes were performed with and without modulators and after GSH depletion. Similar accumulation of (99m)Tc-glucarate was observed in the two cell lines, and the use of MDR reversals did not enhance its uptake. Our results clearly demonstrate that (99m)Tc-glucarate uptake is not related to MRP-1 expression or GSH levels. In contrast, (99m)Tc- MIBI accumulation is inversely proportional to the cell MDR phenotype. The combination of (99m)Tc-glucarate and (99m)Tc-MIBI may be a useful tool for the noninvasive detection of malignant sites and their chemoresistance status.