Figure 3.

Impaired glymphatic system and IPAD in ischemic stroke and therapeutic targets.

Possible mechanisms of glymphatic dysfunction following cerebral ischemia: (1) Decreased arterial pulsation due to vessel occlusion reduces the driving force; (2) Enlarged perivascular space is associated with aggravated cytotoxic edema; (3) Changes in AQP4 expression and distribution are involved in cerebral edema formation and resolution, as well as solute clearance deficiency; (4) Swelling astrocytes restrict the flexibility of fluid flow. The pathological changes of IPAD following cerebral ischemia include damaged smooth muscle cells and basement membrane degradation. As for therapeutic targets, AQP4 is a promising target for glymphatic function improvement and edema amelioration. Potential treatment strategies may include inhibition of AQP4 function, regulation of AQP4 expression and restoration of AQP4 polarization. Drugs that modulate SMC function can facilitate the IPAD clearance pathway and may be beneficial for preventing the cognitive impairment observed after stroke. AQP4: Aquaporin-4; IPAD: intramural periarterial drainage; SMC: smooth muscle cell.