title: Greatly improved survival and neuroprotection in aquaporin-4-knockout mice following global cerebral ischemia.
abstract: Aquaporin-4 (AQP4), the principal water channel in astrocytes, is involved in brain water movement, inflammation, and neuroexcitation. In this study, there was strong neuroprotection in mice lacking AQP4 in a model of global cerebral ischemia produced by transient, bilateral carotid artery occlusion (BCAO). Survival and neurological outcome were greatly improved in the AQP4(-/-) vs. AQP4(+/+) mice after occlusion, with large and robust differences in both outbred (CD1) and inbred (C57bl/6) mouse strains without or with mechanical ventilation. Improved survival was also seen in mice lacking the scaffold protein α-syntrophin, which manifest reduced astrocyte water permeability secondary to defective AQP4 plasma membrane targeting. Intracranial pressure elevation and brain water accumulation were much reduced in the AQP4(-/-) vs. AQP4(+/+) mice after carotid artery occlusion, as were blood-brain barrier (BBB) disruption and neuronal loss. Brain slices from AQP4(-/-) mice showed significantly reduced cell swelling and cytotoxicity in response to oxygen-glucose deprivation, compared with slices from AQP4(+/+) mice. Our findings suggest that the neuroprotective effect of AQP4 deletion in global cerebral ischemia involves reduced astrocyte swelling and brain water accumulation, resulting in reduced BBB disruption, inflammation, and neuron death. AQP4 water transport inhibition may improve survival and neurological outcome after cardiac arrest and in other conditions associated with global cerebral ischemia.
authors.affiliation: 1University of California, 1246 Health Sciences East Tower, Box 0521, San Francisco, CA 94143-0521, USA; alan.verkman@ucsf.edu.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Katada
authors.forename: Gokhan
authors.initials: G
authors.lastname: Akdemir
authors.forename: Nithi
authors.initials: N
authors.lastname: Asavapanumas
authors.forename: Julien
authors.initials: J
authors.lastname: Ratelade
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007427:Intracranial Pressure / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D051401:Aquaporin 4
keywords: astrocyte; brain swelling; neuroscience; water channel