title: Glucagon-Like Peptide-1 Strengthens the Barrier Integrity in Primary Cultures of Rat Brain Endothelial Cells Under Basal and Hyperglycemia Conditions.
abstract: The objective of the present study was to determine the effects of glucagon-like peptide-1 (GLP-1) on barrier functions and to assess the underlying mechanism using an in vitro blood-brain barrier (BBB) model comprised of a primary culture of rat brain capillary endothelial cells (RBECs). GLP-1 increased transendothelial electrical resistance and decreased the permeability of sodium fluorescein in RBECs in a dose- and time-dependent manner. The effects on these barrier functions were significantly reduced in the presence of the GLP-1 receptor antagonist exendin-3 (9-39) and the protein kinase A (PKA) inhibitor H-89. Western blot analysis showed that GLP-1 increased the amount of occludin and claudin-5. GLP-1 analogs are approved for treatment of type 2 diabetes mellitus, and thus, we examined the effects of GLP-1 on hyperglycemia-induced BBB damage. GLP-1 inhibited the increase in production of reactive oxygen species under hyperglycemia conditions and improved the BBB integrity induced by hyperglycemia. As GLP-1 stabilized the integrity of the BBB, probably via cAMP/PKA signaling, the possibility that GLP-1 acts as a BBB-protective drug should be considered.
authors.affiliation: Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Medical Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. shin3@nagasaki-u.ac.jp.
authors.forename: Shinsuke
authors.identifier: http://orcid.org/0000-0001-7945-9719
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Medical Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Tatsumi
authors.affiliation: Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Morofuji
authors.affiliation: Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Takeshita
authors.affiliation: Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Advanced Medical Education Support Center, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsuo
authors.affiliation: BBB Laboratory, PharmaCo-Cell Company, Ltd., Nagasaki, 1-43 Dejima, Nagasaki, 850-0862, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Niwa
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability; D002478:Cells, Cultured; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors; D005947:Glucose / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D062507:Claudin-5; D000067757:Glucagon-Like Peptide-1 Receptor; D007546:Isoquinolines; D062793:Occludin; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D052216:Glucagon-Like Peptide 1; D005947:Glucose; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Blood-brain barrier; Glucagon-like peptide 1; Hyperglycemia; Tight junctions; cAMP/PKA signaling