MAP Kinase Pathways in Brain Endothelial Cells and Crosstalk with Pericytes and Astrocytes Mediate Contrast-Induced Blood–Brain Barrier Disruption
Yuki Matsunaga,
Shinsuke Nakagawa,
Yoichi Morofuji,
Shinya Dohgu,
Daisuke Watanabe,
Nobutaka Horie,
Tsuyoshi Izumo,
Masami Niwa,
Fruzsina R. Walter,
Ana Raquel Santa-Maria,
Maria A. Deli,
Takayuki Matsuo
Affiliations
Yuki Matsunaga
Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
Shinsuke Nakagawa
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Yoichi Morofuji
Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
Shinya Dohgu
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Daisuke Watanabe
BBB Laboratory, PharmaCo-Cell Company Ltd., Dai-ichi-senshu bldg. 2nd Floor, 6-19 Chitose-machi, Nagasaki 852-8135, Japan
Nobutaka Horie
Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
Tsuyoshi Izumo
Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
Masami Niwa
BBB Laboratory, PharmaCo-Cell Company Ltd., Dai-ichi-senshu bldg. 2nd Floor, 6-19 Chitose-machi, Nagasaki 852-8135, Japan
Fruzsina R. Walter
Biological Barriers Research Group, Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
Ana Raquel Santa-Maria
Biological Barriers Research Group, Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
Maria A. Deli
Biological Barriers Research Group, Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary
Takayuki Matsuo
Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
Neurointervention with contrast media (CM) has rapidly increased, but the impact of CM extravasation and the related side effects remain controversial. This study investigated the effect of CM on blood–brain barrier (BBB) integrity. We established in vitro BBB models using primary cultures of rat BBB-related cells. To assess the effects of CM on BBB functions, we evaluated transendothelial electrical resistance, permeability, and tight junction (TJ) protein expression using immunohistochemistry (IHC) and Western blotting. To investigate the mechanism of iopamidol-induced barrier dysfunction, the role of mitogen-activated protein (MAP) kinases in brain endothelial cells was examined. We assessed the effect of conditioned medium derived from astrocytes and pericytes under iopamidol treatment. Short-term iopamidol exposure on the luminal side induced transient, while on the abluminal side caused persistent BBB dysfunction. IHC and immunoblotting revealed CM decreased the expression of TJ proteins. Iopamidol-induced barrier dysfunction was improved via the regulation of MAP kinase pathways. Conditioned medium from CM-exposed pericytes or astrocytes lacks the ability to enhance barrier function. CM may cause BBB dysfunction. MAP kinase pathways in brain endothelial cells and the interactions of astrocytes and pericytes mediate iopamidol-induced barrier dysfunction. CM extravasation may have negative effects on clinical outcomes in patients.
