Astrocytic aquaporin 4 subcellular translocation as a therapeutic target for cytotoxic edema in ischemic stroke

Brain edema is a common feature of several brain diseases (e.g., stroke, traumatic brain injury, hydrocephalus, brain cancer, and brain infections). Brain edema leads to increased intracranial pressure and worsens outcomes in ischemic stroke patients. Conventional treatments to control brain edema, thus reducing intracranial pressure include different osmotherapeutics, hyperventilation, tromethamine, hypothermia, and barbiturate coma. However, level 1 evidence of efficacy is lacking for these treatments, with some being harmful rather than beneficial (Bardutzky and Schwab, 2007). It has been proposed aquaporin 4 (AQP4) can be a novel drug target for treating brain edema (Vandebroek and Yasui, 2020). AQP4 is a small integral membrane protein and is strongly expressed in the brain. It has a highly polarized expression towards the abluminal side of astrocytic endfeet that surrounds the brain vasculature and is also expressed on the subpial and subependymal astrocyte processes, as well as basolateral membranes of ependymal cells (Patabendige et al., 2021). AQP4 is primarily involved in bidirectional water flux, but also has diverse roles such as Ca2+ signaling, K+ buffering, neuroinflammation, and waste clearance (Verkman et al., 2017). Astroglial water movements induced by AQP4 have been shown to be a driving force contributing to the paravascular clearance of interstitial solutes like amyloid-β, thus participating in the so-called “glymphatic system” (Iliff et al., 2012).