Exploring lipophilic compounds that induce BDNF secretion in astrocytes beyond the BBB using a new multi-cultured human in vitro BBB model

Miwako Fujisawa; Yukio Takeshita; Susumu Fujikawa; Kinya Matsuo; Masashi Okamoto; Masaya Tamada; Fumitaka Shimizu; Yasuteru Sano; Michiaki Koga; Takashi Kanda

doi:10.1016/j.jneuroim.2021.577783

Exploring lipophilic compounds that induce BDNF secretion in astrocytes beyond the BBB using a new multi-cultured human in vitro BBB model

J Neuroimmunol. 2022 Jan 15:362:577783. doi: 10.1016/j.jneuroim.2021.577783. Epub 2021 Dec 6.

Authors

Affiliations

¹ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: fuji0418@yamaguchi-u.ac.jp.
² Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: takeshy@yamaguchi-u.ac.jp.
³ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: smfujika@yamaguchi-u.ac.jp.
⁴ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: matsuok@yamaguchi-u.ac.jp.
⁵ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: i022eb@yamaguchi-u.ac.jp.
⁶ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: i055eb@yamaguchi-u.ac.jp.
⁷ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: fshimizu@yamaguchi-u.ac.jp.
⁸ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: yasuteru@yamaguchi-u.ac.jp.
⁹ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: kogamrk@yamaguchi-u.ac.jp.
¹⁰ Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan. Electronic address: tkanda@yamaguchi-u.ac.jp.

PMID: 34902709
DOI: 10.1016/j.jneuroim.2021.577783

Abstract

Brain-derived neurotrophic factor (BDNF) cannot cross the blood-brain barrier (BBB) when administered peripherally, which hinders its therapeutic potential. We utilized an in vitro BBB model-a tri-culture of a human endothelial cell line, a pericyte cell line, and an astrocyte cell line-to study the effect of twenty candidate lipophilic compounds on stimulating BDNF secretion in pericytes and astrocytes. The prostaglandin E2 receptor 4 agonist and sphingosine-1-phosphate receptor 5 agonist facilitated secretion of BDNF in the astrocyte, but did not decrease the transendothelial electrical resistance. These compounds may be promising agents for neurodegenerative and neuroinflammatory diseases.

Keywords: Astrocyte; Blood-brain barrier; Brain-derived neurotrophic factor; Pericyte; Prostaglandin E2 receptor 4 agonist; Sphingosine-1-phosphate receptor 5 agonist.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Astrocytes / metabolism*
Blood-Brain Barrier*
Brain-Derived Neurotrophic Factor / biosynthesis*
Cells, Cultured
Coculture Techniques / methods*
Humans
Receptors, Prostaglandin E, EP4 Subtype / agonists
Sphingosine-1-Phosphate Receptors / agonists

Substances

Brain-Derived Neurotrophic Factor
Receptors, Prostaglandin E, EP4 Subtype
Sphingosine-1-Phosphate Receptors
BDNF protein, human