Potentiating Cerebral Perfusion Normalizes Glymphatic Dynamics in Systemic Inflammation

The glymphatic system is essential for maintaining fluid homeostasis and clearing metabolic waste in the brain. Existing evidence suggests that this system is disrupted by systemic inflammation; however, the pathological characteristics and mechanisms underlying this disruption remain unclear. Near-infrared II imaging reveals an excessive increase in perivascular cerebrospinal fluid (CSF) influx and a reduction in CSF efflux, accompanied by impaired glymphatic clearance within 72 h in mice intraperitoneally injected with lipopolysaccharide (LPS) at a dose of 5 mg kg^-1, which does not significantly disrupt the blood-brain barrier. An inverse relationship is observed between cerebral blood flow (CBF) and glymphatic influx trends following LPS challenge. Enhancement of CBF via levosimendan effectively ameliorates glymphatic flux and clearance, but these improvements are abolished by bilateral carotid artery stenosis surgery, indicating that cerebral hypoperfusion mediates LPS-induced glymphatic dysfunction. Furthermore, levosimendan administration attenuates LPS-induced neuroinflammation and neurological deficits. Mechanistically, CBF augmentation prevents the LPS-induced perivascular Aquaporin-4 (AQP4) depolarization, whereas the AQP4 inhibitor TGN-020 blocks its beneficial effects on both amyloid-β clearance and neuroinflammation suppression, confirming AQP4's pivotal role. Behaviorally, levosimendan ameliorates LPS-induced neurological deficits. These findings establish cerebral hypoperfusion as a key mediator of systemic inflammation-induced glymphatic dysfunction, revealing a promising therapeutic avenue for sepsis-associated encephalopathy.