Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood-brain barrier: [ 17 O]H 2 O JJVCPE MRI study

Vincent J. Huber, Hironaka Igarashi, Satoshi Ueki, Ingrid Kwee, Tsutomu Nakada

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The blood-brain barrier (BBB), which imposes significant water permeability restriction, effectively isolates the brain from the systemic circulation. Seemingly paradoxical, the abundance of aquaporin-4 (AQP-4) on the inside of the BBB strongly indicates the presence of unique water dynamics essential for brain function. On the basis of the highly specific localization of AQP-4, namely, astrocyte end feet at the glia limitans externa and pericapillary Virchow-Robin space, we hypothesized that the AQP-4 system serves as an interstitial fluid circulator, moving interstitial fluid from the glia limitans externa to pericapillary Virchow-Robin space to ensure proper glymphatic flow draining into the cerebrospinal fluid. The hypothesis was tested directly using the AQP-4 facilitator TGN-073 developed in our laboratory, and [ 17 O]H 2 O JJ vicinal coupling proton exchange MRI, a method capable of tracing water molecules delivered into the blood circulation. The results unambiguously showed that facilitation of AQP-4 by TGN-073 increased turnover of interstitial fluid through the system, resulting in a significant reduction in [ 17 O]H 2 O contents of cortex with normal flux into the cerebrospinal fluid. The study further suggested that in addition to providing the necessary water for proper glymphatic flow, the AQP-4 system produces a water gradient within the interstitial space promoting circulation of interstitial fluid within the BBB.

Original languageEnglish (US)
Pages (from-to)697-703
Number of pages7
JournalNeuroReport
Volume29
Issue number9
DOIs
StatePublished - Jan 1 2018

Keywords

  • glia limitans externa
  • glymphatic flow
  • Virchow-Robin space
  • Xenopus laevis

ASJC Scopus subject areas

  • Neuroscience(all)

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