Targeted overexpression of endothelin-1 in astrocytes leads to more severe cytotoxic brain edema and higher mortality.
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.
Yeung
Patrick Ka Kit
PK
Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 852, Hong Kong, China.
Lo
Amy Cheuk Yin
AC
Leung
Justin Wai Chung
JW
Chung
Stephen Sum Man
SS
Chung
Sookja Kim
SK
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
D065092:Antidiuretic Hormone Receptor Antagonists; D051401:Aquaporin 4; D001552:Benzazepines; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D014867:Water; C076251:mozavaptan