Possible Role of Glymphatic System of the Brain in the Pathogenesis of High-Altitude Cerebral Edema

In this article, we suggest that the glymphatic system of the brain can play an important role in the pathogenesis of high-altitude cerebral edema (HACE). Water enters the intercellular space of the brain primarily through aquaporin-4 (AQP-4) water channels, the main component of the glymphatic system, whereas acetazolamide, pharmacological agent used in the prevention of HACE, is the blocker of the AQP-4 molecule. In animal experiments, cerebral edema caused by hypobaric hypoxia was associated with an increased expression of AQP-4 by astrocytes. Also, the glymphatic system is primarily active during sleep, although sleep at high altitude is a well-known risk factor of developing HACE. All these findings support our hypothesis. We suggest that future research on the prevention and treatment of HACE should involve factors that are already known to modify activity of the glymphatic system, such as angiotensin-converting enzyme inhibitors or other pharmaceutical agents affecting noradrenergic system of the brain, body posture during sleep, anatomy of the veins draining the cranial cavity, and the influence of physical activity before and during exposure to high altitude, especially in relation to sleep.