Potentiating Cerebral Perfusion Normalizes Glymphatic Dynamics in Systemic Inflammation

Area of Science:

• Neuroscience
• Immunology
• Physiology

Background:

• The glymphatic system clears brain waste but is disrupted by inflammation.
• Mechanisms of inflammation-induced glymphatic dysfunction are poorly understood.

Purpose of the Study:

• Investigate how systemic inflammation affects the glymphatic system.
• Identify therapeutic targets for inflammation-induced glymphatic dysfunction.

Main Methods:

• Near-infrared II imaging in mice treated with lipopolysaccharide (LPS).
• Assessment of cerebrospinal fluid (CSF) influx/efflux, glymphatic clearance, and cerebral blood flow (CBF).
• Intervention with levosimendan (CBF enhancer) and AQP4 inhibition.

Main Results:

• LPS increased CSF influx, reduced efflux, and impaired glymphatic clearance.
• Reduced CBF correlated with glymphatic dysfunction.
• Levosimendan improved glymphatic function and reduced neuroinflammation, effects abolished by carotid stenosis.
• CBF augmentation prevented AQP4 depolarization; AQP4 inhibition blocked therapeutic benefits.

Conclusions:

• Cerebral hypoperfusion mediates inflammation-induced glymphatic dysfunction.
• Targeting CBF and AQP4 offers a therapeutic strategy for sepsis-associated encephalopathy.