title: Improvement of cold injury-induced mouse brain edema by endothelin ETB antagonists is accompanied by decreases in matrixmetalloproteinase 9 and vascular endothelial growth factor-A.
abstract: Brain edema is a potentially fatal pathological state that often occurs after brain injuries such as ischemia and trauma. However, therapeutic agents that fundamentally treat brain edema have not yet been established. We previously found that endothelin ETB receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice. In this study, the effects of ETB antagonists on matrixmetalloproteinase (MMP)9 and vascular endothelial growth factor (VEGF)-A expression were examined in the cold injury model. Cold injury was performed in the left brain of male ddY mice (5-6 weeks old) for the induction of vasogenic edema. Expression of MMP9 and VEGF-A mRNA in the mouse cerebrum was increased by cold injury. Immunohistochemical observations showed that the MMP9 and VEGF-A were mainly produced in reactive astrocytes in the damaged cerebrum. Intracerebroventricular administration of BQ788 (10 μg) or IRL-2500 (10 μg) (selective ETB antagonists) attenuated brain edema and disruption of the blood-brain barrier after cold injury. BQ788 and IRL-2500 reversed the cold injury-induced increases in MMP9 and VEGF-A expression. The induction of reactive astrocytes producing MMP9 and VEGF-A in the damaged cerebrum was attenuated by BQ788 and IRL-2500. These results suggest that attenuations of astrocytic MMP9 and VEGF-A expression by ETB antagonists may be involved in the amelioration of vasogenic brain edema.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Michinaga
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Seno
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Fuka
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Shizuho
authors.initials: S
authors.lastname: Minami
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Kimura
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Hatanaka
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Nagase
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Matsuyama
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamanaka
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tonda-bayashi, Osaka, 584-8540, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Koyama
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage; D001929:Brain Edema / Q000378:metabolism* / Q000517:prevention & control; D054022:Cerebrum / Q000293:injuries / Q000378:metabolism*; D000067390:Cold Injury / Q000378:metabolism* / Q000517:prevention & control; D004151:Dipeptides / Q000008:administration & dosage; D065131:Endothelin B Receptor Antagonists / Q000008:administration & dosage*; D007276:Injections, Intraventricular; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D001713:Biphenyl Compounds; D004151:Dipeptides; D065131:Endothelin B Receptor Antagonists; C098287:IRL 2500; D009842:Oligopeptides; D010880:Piperidines; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C086539:BQ 788; D020780:Matrix Metalloproteinase 9
keywords: astrocyte; blood-brain barrier; brain injury; vascular permeability factors