Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood-brain barrier: [17O]H2O JJVCPE MRI study

Neuroreport. 2018 Jun 13;29(9):697-703. doi: 10.1097/WNR.0000000000000990.


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 [O]H2O 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 [O]H2O 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4 / metabolism
  • Blood-Brain Barrier / diagnostic imaging*
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology
  • Central Nervous System Agents / chemical synthesis
  • Central Nervous System Agents / pharmacology*
  • Extracellular Fluid / diagnostic imaging*
  • Extracellular Fluid / drug effects*
  • Hemodynamics
  • Magnetic Resonance Imaging / methods
  • Male
  • Mice, Inbred C57BL
  • Oocytes
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology*
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology*
  • Water / metabolism
  • Xenopus laevis


  • Aquaporin 4
  • Central Nervous System Agents
  • Pyridines
  • Sulfonamides
  • Water