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Improvement of cold injury‐induced mouse brain edema by endothelin ET B antagonists is accompanied by decreases in matrixmetalloproteinase 9 and vascular endothelial growth factor‐A
Author(s) -
Michinaga Shotaro,
Seno Naoki,
Fuka Mayu,
Yamamoto Yui,
Minami Shizuho,
Kimura Akimasa,
Hatanaka Shunichi,
Nagase Marina,
Matsuyama Emi,
Yamanaka Daisuke,
Koyama Yutaka
Publication year - 2015
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.13020
Subject(s) - endothelin 1 , endothelin receptor , edema , medicine , brain edema , vascular endothelial growth factor , receptor , vegf receptors
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 ET B receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice. In this study, the effects of ET B 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 MMP 9 and VEGF ‐A mRNA in the mouse cerebrum was increased by cold injury. Immunohistochemical observations showed that the MMP 9 and VEGF ‐A were mainly produced in reactive astrocytes in the damaged cerebrum. Intracerebroventricular administration of BQ 788 (10 μg) or IRL ‐2500 (10 μg) (selective ET B antagonists) attenuated brain edema and disruption of the blood–brain barrier after cold injury. BQ 788 and IRL ‐2500 reversed the cold injury‐induced increases in MMP 9 and VEGF ‐A expression. The induction of reactive astrocytes producing MMP 9 and VEGF ‐A in the damaged cerebrum was attenuated by BQ 788 and IRL ‐2500. These results suggest that attenuations of astrocytic MMP 9 and VEGF ‐A expression by ET B antagonists may be involved in the amelioration of vasogenic brain edema.