Aquaporin-4 depolarization in stroke: Mechanisms and therapeutic implications

Cerebral edema is a life-threatening complication of stroke, yet its underlying mechanisms remain incompletely understood, hindering the development of effective therapies. Aquaporin-4 (AQP4), the principal water channel of the glymphatic system, is crucial for cerebral water homeostasis. Following a stroke, AQP4 undergoes pathological depolarization-a loss of its polarized localization on astrocytic endfeet. This review establishes AQP4 depolarization as a central, unifying event that orchestrates secondary brain injury in stroke. We systematically dissect how AQP4 depolarization disrupts both glymphatic clearance and blood-brain barrier (BBB) integrity, thereby fueling a vicious cycle of edema formation. A key insight we advance is the divergent pathophysiology between stroke subtypes: in ischemic stroke, AQP4 depolarization drives initial glymphatic failure and cytotoxic edema, which subsequently promotes BBB breakdown and vasogenic edema. Conversely, in hemorrhagic stroke, primary vasogenic edema triggers AQP4 depolarization, which then mediates secondary glymphatic impairment and cytotoxic edema. Based on this mechanistic framework, we critically evaluate emerging interventions aimed at preserving AQP4 polarity. We conclude that maintaining AQP4 polarization, rather than non-selectively inhibiting its channel function, represents a paradigm shift and a more precise neuroprotective strategy for combating stroke-induced cerebral edema.