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

 Proposed interventions to modulate the glymphatic system in cerebral ischemia.

StrategyProposed mechanismExperimental evidenceLimitationsAnalytic considerations
Arterial pulsation stimulation (dobutamine)Increase glymphatic flow and metabolite clearanceImproves clearance in the human brain [40]Hypertension prevents humans from usingWhile animal studies suggest improved metabolic clearance, clinical application is limited by cardiovascular risk.
DigoxinIncrease cardiac output without raising blood pressureImproves vascular pulsations and glymphatic function in chronic hypoperfusion [12]Unclear if the effect is direct on cerebral blood flowPotential benefits might be indirect, related to improved cardiac function rather than direct cerebral effects.
AQP-4 inhibition (TGN-020)Reduce water and ion influx into parenchymaDecreases early cytotoxic edema [44]Non-selective; may impair venous clearancePromising in early ischemia, but prolonged inhibition could compromise physiological drainage. Future research should focus on transient or more selective modulators of AQP-4.
Strict blood pressure controlPossible reduction of oxidative stress-induced AQP-4 upregulationLess neurological deterioration [46]Lack of direct evidence on GSStrict blood pressure control is already standard in clinical care, but its direct impact on glymphatic clearance remains uncertain.
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AQP-4: aquaporin-4; TGN-020: N-(1,3,4-thiadiazol-2-yl) pyridine-3-carboxamide dihydrochloride.