title: Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice.
abstract: A hallmark of stroke is water accumulation (edema) resulting from dysregulation of osmotic homeostasis. Brain edema contributes to tissue demise and may lead to increased intracranial pressure and lethal herniation. Currently, there are only limited treatments to prevent edema formation following stroke. Aquaporin 4 (AQP4), a brain water channel, has become a focus of interest for therapeutic approaches targeting edema. At present, there are no pharmacological tools to block AQP4. The role of AQP4 in edema after brain injury remains unclear with conflicting results from studies using AQP4-/-mice and of AQP4 expression following stroke. Here, we studied AQP4 and its role in edema formation by testing AQP4-/-mice in a model of middle cerebral artery occlusion using novel quantitative MRI water content measurements, histology and behavioral changes as outcome measures. Absence of AQP4 was associated with decreased mortality and increased motor recovery 3 to 14 days after stroke. Behavioral improvement was associated with decreased lesion volume, neuronal cell death and neuroinflammation in AQP4-/-compared to wild type mice. Our data suggest that the lack of AQP4 confers an overall beneficial role at long term with improved neuronal survival and reduced neuroinflammation, but without a direct effect on edema formation.
authors.affiliation: Department of Clinical Neurosciences, Neurology Service, Centre Hospitalier Universitaire Vaudois and Lausanne University, Switzerland.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Hirt
authors.affiliation: Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fukuda
authors.affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Kamalakar
authors.initials: K
authors.lastname: Ambadipudi
authors.affiliation: Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Faisil
authors.initials: F
authors.lastname: Rashid
authors.affiliation: Center for Glial-Neuronal Interactions, Division of Biomedical Sciences, University of California, Riverside, Riverside, CA, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: Binder
authors.affiliation: Medicine and Physiology, Cardiovascular Research Institute, University of California San Francisco, CA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Verkman
authors.affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ashwal
authors.affiliation: Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA.|Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.|Center for Glial-Neuronal Interactions, Division of Biomedical Sciences, University of California, Riverside, Riverside, CA, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Obenaus
authors.affiliation: Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA Jerome.badaut@u-bordeaux.fr.|Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.|CNRS UMR5287, University of Bordeaux, Bordeaux, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Badaut
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D001929:Brain Edema / Q000000981:diagnostic imaging / Q000209:etiology* / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications* / Q000628:therapy; D016923:Cell Death / Q000187:drug effects; D004660:Encephalitis; D020244:Infarction, Middle Cerebral Artery; D002546:Ischemic Attack, Transient / Q000150:complications* / Q000628:therapy; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D051401:Aquaporin 4
keywords: Aquaporin; astrocyte; blood-brain barrier; stroke; transient middle cerebral artery occlusion