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

Autor: Giannetto MJ; Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.; Department of Neuroscience, University of Rochester Medical Center, Rochester, New York, USA., Gomolka RS; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Gahn-Martinez D; Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA., Newbold EJ; Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.; Department of Neuroscience, University of Rochester Medical Center, Rochester, New York, USA., Bork PAR; Department of Physics, Technical University of Denmark, Lyngby, Denmark., Chang E; Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA., Gresser M; Aeromics Inc., New Haven, Connecticut, USA., Thompson T; Aeromics Inc., New Haven, Connecticut, USA., Mori Y; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Nedergaard M; Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Glia [Glia] 2024 May; Vol. 72 (5), pp. 982-998. Date of Electronic Publication: 2024 Feb 16.
DOI: 10.1002/glia.24515
Abstrakt: 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.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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