Current AQP research: therapeutic approaches to ischemic and hemorrhagic stroke

The role of aquaporins (AQPs) in the formation of cerebral edema after stroke: Stroke can be classified into either ischemic or hemorrhagic based on their etiological mechanism. Cerebral edema development often accompanies both ischemic infarct and intracerebral hemorrhage (ICH). Cerebral edema is differentiated according to their underlying mechanism and time course: cytotoxic and vasogenic. Currently, the only approved therapies for treating cerebral edema include decompressive craniectomy and osmotherapy, which both aim to alleviate the downstream effects, rather than addressing the molecular mechanisms underlying edema development (Stokum et al., 2015). Aquaporins (AQPs) are a class of water channel proteins which have been implicated in the regulation of both physiological and pathological water homeostasis, and represent a promising target for alleviating stroke-induced cerebral edema. Thus far, 13 mammalian AQPs have been identified to be heterogeneously expressed in various tissues. Seven types of AQPs (AQP1, AQP3, AQP4, AQP5, AQP8, AQP9, AQP11) have been found to be expressed in the mammalian central nervous system (CNS), with AQP4 being the dominant AQP channel present in the mammalian brain (Vella et al., 2015). AQP4 is a bidirectional water-specific channel which is primarily concentrated within the glial limitans and astrocytic endfeet in association with the vasculature at the division between the brain parenchyma and major fluid compartments, such as the blood-brain barrier (BBB). AQP4 plays a role in mediating water influx during the manifestation of edema as well as regulating water efflux during clearance. AQP4 expression is both spatially and temporally regulated based on the type of stroke model, with AQP4 downregulation noted in cytotoxic edema and an upregulation observed at the onset of vasogenic edema, potentially serving to accelerate water clearance (Stokum et al., 2015). AQP4 upregulation plays a significant role in the formation of vasogenic edema following both hemorrhagic and late ischemic stroke. Cytotoxic edema, which appears during the early stages of ischemic stroke, is correlated with a downregulation of AQP4 expression (Ribeiro Mde et al., 2006; Zhao et al., 2016), while AQP1 and AQP9 are both upregulated following ICH (Wang et al., 2015). ICH is typically associated with the development of vasogenic edema. In cases of ischemic stroke, edema formation proceeds in a cascade, wherein cytotoxic edema manifests during the first few hours following the ischemic insult. Subsequent prolonged periods of ischemia can prompt the breakdown of the BBB and the hemorrhagic conversion of ischemic tissue, resulting in a progression from cytotoxic to vasogenic edema. Cytotoxic edema often occurs in the early stages of ischemic stroke with AQP4 downregulation. Cytotoxic cerebral edema manifests as AQP4 facilitates water passage into the astrocyte compartment, causing cellular swelling and disruption of the basal lamina. The downregulation of AQP4 at this stage may be a response to counteract the influx of water and resultant cerebral swelling. In cases of hemorrhagic stroke and the late stages of ischemic stroke, BBB disruption results in vasogenic edema. Water accumulates in the extracellular space (ECS) after exiting the leaky capillaries. Concurrently, AQP4 channels in the astrocyte endfeet are upregulated, which gradually facilitates the removal of extracellular fluid.