The role of the glymphatic system in cerebral ischemia: pathological implications and future perspectives

The glymphatic system (GS) consists of a paravascular fluid-exchange network that regulates cerebrospinal and interstitial fluid dynamics, clears metabolic waste, and modulates neuroinflammation. Aquaporin-4 (AQP-4), expressed in astrocytic end-feet, is central to GS function and blood-brain barrier integrity, but in cerebral ischemia (CI), GS disruption and AQP-4 mislocalization drive cytotoxic edema, inflammation, and vascular dysfunction, worsening outcomes. This review aimed to examine the role of the GS in CI, focusing on pathophysiology and potential therapeutic targets. A PubMed-based literature review was conducted, selecting 51 studies from 115 screened that addressed GS, AQP-4, and ischemic stroke. Evidence suggests that modulating GS flow, through strategies such as enhancing arterial pulsations or regulating AQP-4, may reduce edema and neuroinflammation, although selectively targeting AQP-4 without impairing waste clearance remains a key challenge. The GS represents a promising therapeutic target in ischemic stroke, and a deeper understanding of its physiology may guide the development of neuroprotective interventions; future research should refine pharmacological strategies to optimize glymphatic function and improve recovery in CI patients.