Glymphatic system impairment contributes to the formation of brain edema after ischemic stroke

Abstract The blood-brain barrier (BBB) damage has traditionally been considered to determine the occurrence and development of post-stroke brain edema, a devastating and life-threatening complication. However, no treatment strategy targeting BBB damage has been proven clinically effective in ameliorating brain edema. Here, we found that the extravasation of protein-rich fluids into the brain was not temporally correlated with edema formation after middle cerebral artery occlusion (MCAO) in mice, as brain edema reabsorption preceded BBB closure. Strikingly, the time course of edema progression matched well with the glymphatic system (GS) dysfunction after MCAO. Pharmacological enhancement of the GS function significantly alleviated brain edema developed on day 2 after MCAO, accompanied by less deposition of Aβ and better cognitive function. Conversely, functional suppression of the GS delayed the absorption of brain edema on day 7 after MCAO. Moreover, patients with ischemic stroke revealed a consistent trend of GS dysfunction after reperfusion as MCAO mice, which was correlated with the severity of brain edema and functional outcomes. Collectively, these findings indicate that the GS is a key contributor to the formation of brain edema after ischemic stroke, and targeting the GS may be a promising strategy for the treatment of brain edema in ischemic stroke. One Sentence Summary The function of the glymphatic system is a key factor in determining the formation or resolution of brain edema after ischemic stroke Graphical Abstract