Cardiac glycosides target barrier inflammation of the vasculature, meninges and choroid plexus

Deidre Jansson,Emma Scotter,Rebecca Johnson,Victor Birger Dieriks,Mike Dragunow,Edward Mee,Justin Rustenhoven,Maurice Curtis,Sheryl Feng,Miranda Aalderink,Patrick Schweder,Richard Faull,Peter Heppner,Leon C D Smyth,Clinton Turner

doi:10.1038/s42003-021-01787-x

Abstract

Neuroinflammation is a key component of virtually all neurodegenerative diseases, preceding neuronal loss and associating directly with cognitive impairment. Neuroinflammatory signals can originate and be amplified at barrier tissues such as brain vasculature, surrounding meninges and the choroid plexus. We designed a high content screening system to target inflammation in human brain-derived cells of the blood–brain barrier (pericytes and endothelial cells) to identify inflammatory modifiers. Screening an FDA-approved drug library we identify digoxin and lanatoside C, members of the cardiac glycoside family, as inflammatory-modulating drugs that work in blood–brain barrier cells. An ex vivo assay of leptomeningeal and choroid plexus explants confirm that these drugs maintain their function in 3D cultures of brain border tissues. These results suggest that cardiac glycosides may be useful in targeting inflammation at border regions of the brain and offer new options for drug discovery approaches for neuroinflammatory driven degeneration.

Highlights

Neuroinflammation is a key component of virtually all neurodegenerative diseases, preceding neuronal loss and associating directly with cognitive impairment
We have demonstrated that pericytes derived from post-mortem human brains display a robust inflammatory response when stimulated by classical inflammatory mediators such as tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin 1β (IL-1β) and lipopolysaccharide (LPS), and are likely to be targets of neuroinflammation in both an autocrine and paracrine fashion[18,19]
Primary human brain pericytes respond to inflammatory stimuli to induce the expression of chemokines and adhesion molecules, including chemokine (C-C motif) ligand 2 (CCL2) and intercellular adhesion molecule-1 (ICAM-1), respectively[18,41,42,43]

Summary

Introduction

Neuroinflammation is a key component of virtually all neurodegenerative diseases, preceding neuronal loss and associating directly with cognitive impairment. An ex vivo assay of leptomeningeal and choroid plexus explants confirm that these drugs maintain their function in 3D cultures of brain border tissues These results suggest that cardiac glycosides may be useful in targeting inflammation at border regions of the brain and offer new options for drug discovery approaches for neuroinflammatory driven degeneration. Accumulating evidence suggests an inflammatory contribution by cells of the cerebrovasculature, meningeal compartments and choroid plexus (ChP), which facilitate immune cell trafficking across the barriers[6,7,8]. In addition to primary human brain neurovascular cells such as pericytes, endothelia cells and microglia, we made use of explants from barrier tissues such as meninges and ChP, which are directly involved in inflammation. Meningeal-derived factors can permeate the brain parenchyma, presumably through glymphatic exchange, suggesting that modulating meningeal-derived inflammation represents an appropriate target to prevent inflammatory-mediated CNS insults[33,34]

Methods

Results

Conclusion