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A simple novel approach for detecting blood-brain barrier permeability using GPCR internalization.

Authors
  • Csaba, Zsolt1
  • Vitalis, Tania1
  • Charriaut-Marlangue, Christiane1
  • Margaill, Isabelle2
  • Coqueran, Bérard2
  • Leger, Pierre-Louis1
  • Parente, Iolanda1
  • Jacquens, Alice1
  • Titomanlio, Luigi1
  • Constans, Charlotte3
  • Demene, Charlie3
  • Santin, Mathieu D4
  • Lehericy, Stéphane4
  • Perrière, Nicolas5
  • Glacial, Fabienne5
  • Auvin, Stéphane1
  • Tanter, Mickaël3
  • Ghersi-Egea, Jean-François6
  • Adle-Biassette, Homa1, 7
  • Aubry, Jean-François3
  • And 2 more
  • 1 NeuroDiderot, Inserm U1141, Université de Paris, F-75019, Paris, France. , (France)
  • 2 Research Team "Pharmacology of Cerebral Circulation" EA4475, Faculté de Pharmacie de Paris, Université de Paris, F-75006, Paris, France. , (France)
  • 3 Institut Langevin, ESPCI Paris, PSL Research University, CNRS, UMR7587, Inserm U979, Inserm Technology Research Accelerator in Biomedical Ultrasound, Université de Paris, F-75005, Paris, France. , (France)
  • 4 Brain and Spine Institute-ICM, Center for NeuroImaging Research - CENIR, Sorbonne Paris Cité, UPMC Université Paris 06, CNRS, UMR 7225, Inserm U1127, F-75013, Paris, France. , (France)
  • 5 BrainPlotting, Brain and Spine Institute-ICM, F-75013, Paris, France. , (France)
  • 6 Fluid Team, Lyon Neurosciences Research Center, Inserm U1028, CNRS, UMR5292, University Lyon-1, F-69622, Villeurbanne, France. , (France)
  • 7 Service d'Anatomie et de Cytologie Pathologiques, Hôpital Lariboisière, APHP, F-75010, Paris, France. , (France)
Type
Published Article
Journal
Neuropathology and applied neurobiology
Publication Date
Sep 08, 2020
Identifiers
DOI: 10.1111/nan.12665
PMID: 32898926
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Impairment of blood-brain barrier (BBB) is involved in numerous neurological diseases from developmental to aging stages. Reliable imaging of increased BBB permeability is therefore crucial for basic research and preclinical studies. Today, the analysis of extravasation of exogenous dyes is the principal method to study BBB leakage. However, these procedures are challenging to apply in pups and embryos and may appear difficult to interpret. Here we introduce a novel approach based on agonist-induced internalization of a neuronal G protein-coupled receptor widely distributed in the mammalian brain, the somatostatin receptor type 2 (SST2). The clinically approved SST2 agonist octreotide (1 kDa), when injected intraperitoneally does not cross an intact BBB. At sites of BBB permeability, however, OCT extravasates and induces SST2 internalization from the neuronal membrane into perinuclear compartments. This allows an unambiguous localization of increased BBB permeability by classical immunohistochemical procedures using specific antibodies against the receptor. We first validated our approach in sensory circumventricular organs which display permissive vascular permeability. Through SST2 internalization, we next monitored BBB opening induced by magnetic resonance imaging-guided focused ultrasound in murine cerebral cortex. Finally, we proved that after intraperitoneal agonist injection in pregnant mice, SST2 receptor internalization permits analysis of BBB integrity in embryos during brain development. This approach provides an alternative and simple manner to assess BBB dysfunction and development in different physiological and pathological conditions. This article is protected by copyright. All rights reserved.

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