title: Targeted overexpression of endothelin-1 in astrocytes leads to more severe cytotoxic brain edema and higher mortality.
abstract: Transgenic mice overexpressing endothelin-1 (ET-1) in astrocytes (GET-1) displayed more severe brain edema and neurologic dysfunction after experimental ischemic stroke. However, it was not clear whether astrocytic ET-1 contributed to cytotoxic or vasogenic edema associated with stroke. In this study, the role of astrocytic ET-1 in cytotoxic edema and brain injury was investigated. Upon acute water intoxication, the GET-1 mice had a lower survival rate and more severe neurologic deficits. Such an exacerbated condition in the GET-1 mice may be a result of a significant increase in cerebral water content and increased expression of the water channel protein, aquaporin 4 (AQP-4). The GET-1 mice treated with OPC-31260, a nonpeptide arginine vasopressin V(2) receptor antagonist, were alleviated from the cerebral water accumulation and neurologic deficit during the early time period after water intoxication. In addition, a significant reduction of AQP-4 expression was observed in astrocytic end-feet AQP-4 in the hippocampus of the GET-1 mice treated with OPC-31260. Therefore, ET-1-induced AQP-4 expression and cerebral water accumulation are the key factors in brain edema associated with acute water intoxication. The V(2) receptor antagonist, OPC-31260, may be one of the effective drugs for the early treatment of ET-1-induced cytotoxic edema and brain injury.
authors.affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 852, Hong Kong, China.
authors.forename: Patrick Ka Kit
authors.initials: PK
authors.lastname: Yeung
authors.forename: Amy Cheuk Yin
authors.initials: AC
authors.lastname: Lo
authors.forename: Justin Wai Chung
authors.initials: JW
authors.lastname: Leung
authors.forename: Stephen Sum Man
authors.initials: SS
authors.lastname: Chung
authors.forename: Sookja Kim
authors.initials: SK
authors.lastname: Chung
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D001552:Benzazepines / Q000627:therapeutic use; D001921:Brain / Q000503:physiopathology; D001929:Brain Edema / Q000139:chemically induced / Q000503:physiopathology*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015854:Up-Regulation; D014867:Water / Q000378:metabolism; D014869:Water Intoxication / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4; D001552:Benzazepines; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D014867:Water; C076251:mozavaptan