Glymphatic fluid transport is suppressed by the aquaporin‐4 inhibitor AER‐271

Feb 16, 2024Glia

Blocking aquaporin-4 reduces glymphatic fluid flow

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Abstract

Administration of AER-271 resulted in a decrease in glymphatic fluid transport in mouse brain.

Glymphatic fluid transport is crucial for clearing metabolic waste from the brain.
AER-271 inhibited glymphatic influx of cerebrospinal fluid as measured by a tracer method.
Inhibition of AQP4 function with AER-271 also reduced interstitial fluid volume, indicated by diffusion-weighted MRI.
The compound further decreased glymphatic efflux as shown by an in vivo clearance assay.
AER-271 did not alter the localization of AQP4 and showed no effect in mice lacking AQP4.

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The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain.

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