Role of Aquaporin-4 Water Channels in Cerebral Edema After Ischemic Stroke

Persistent Link:
http://hdl.handle.net/10150/194063
Title:
Role of Aquaporin-4 Water Channels in Cerebral Edema After Ischemic Stroke
Author:
Migliati, Elton
Issue Date:
2006
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Stroke is the third leading cause of death and disability in US. Cerebral edema is a major consequence of brain ischemia. Despite the importance of cerebral edema, no effective pharmacological treatments have been developed.Previous research indicates that the aquaporin-4 channel facilitates water movement during cerebral edema formation. Mice lacking the normal expression of aquaporin-4 have decreased cerebral edema, reduced infarct formation and improved neurological outcome induced for classic models of cerebral edema (1, 2, 3). To our knowledge, no compounds that effectively block water permeability through aquaporin-4 have been discovered.My hypothesis is that an aquaporin-4 blocker would significantly decrease the cerebral edema formation after ischemic stroke in mice. My objective was to identify and characterize a novel aquaporin-4 blocker using Xenopus laevis. I also proposed that dystrophin deficient mice, a mouse strain that has a decreased expression of aquaporin-4 channels would have a decrease formation of cerebral edema after transient ischemic stroke when compared with a strain matched controls.I found that bumetanide, a well-described Na+, K+, Cl- cotransporter inhibitor, reversibly and dose dependently inhibited water permeability through aquaporin-4 channels. These results indicated that the protective effect of bumetanide seen in rats after ischemic stroke (4) might be through a combined effect on aquaporin-4 channels and the Na+, K+, Cl- cotransporter.In order to identify the relative amount of protection conferred from the aquaporin-4 channels compared to the Na+, K+, Cl- cotransporter, I characterized the dystrophin deficient mouse after ischemic stroke. I found that dystrophin-deficient mice had a decrease in the formation of cerebral edema after transient brain ischemia when compared with strain-matched controls. Dystrophin-deficient mice had an increased mortality and seizure-like activity after transient brain ischemia. One hypothetical mechanism might be that increased plasma potassium is associated with a presumably decreased ability to buffer potassium after neuronal stimulation, due to its lack of aquaporin-4 and potassium channels (Kir4.1) at the end feet of astrocytes. Because of these additional effects, I concluded that the mdx mouse is not an ideal model for the study of a protective effect of an aquaporin-4 blocker after ischemic stroke.
Type:
text; Electronic Dissertation
Keywords:
Physiological Sciences
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Physiological Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Yool, Andrea J; Ritter, Leslie S
Committee Chair:
Yool, Andrea J; Ritter, Leslie S

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleRole of Aquaporin-4 Water Channels in Cerebral Edema After Ischemic Strokeen_US
dc.creatorMigliati, Eltonen_US
dc.contributor.authorMigliati, Eltonen_US
dc.date.issued2006en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractStroke is the third leading cause of death and disability in US. Cerebral edema is a major consequence of brain ischemia. Despite the importance of cerebral edema, no effective pharmacological treatments have been developed.Previous research indicates that the aquaporin-4 channel facilitates water movement during cerebral edema formation. Mice lacking the normal expression of aquaporin-4 have decreased cerebral edema, reduced infarct formation and improved neurological outcome induced for classic models of cerebral edema (1, 2, 3). To our knowledge, no compounds that effectively block water permeability through aquaporin-4 have been discovered.My hypothesis is that an aquaporin-4 blocker would significantly decrease the cerebral edema formation after ischemic stroke in mice. My objective was to identify and characterize a novel aquaporin-4 blocker using Xenopus laevis. I also proposed that dystrophin deficient mice, a mouse strain that has a decreased expression of aquaporin-4 channels would have a decrease formation of cerebral edema after transient ischemic stroke when compared with a strain matched controls.I found that bumetanide, a well-described Na+, K+, Cl- cotransporter inhibitor, reversibly and dose dependently inhibited water permeability through aquaporin-4 channels. These results indicated that the protective effect of bumetanide seen in rats after ischemic stroke (4) might be through a combined effect on aquaporin-4 channels and the Na+, K+, Cl- cotransporter.In order to identify the relative amount of protection conferred from the aquaporin-4 channels compared to the Na+, K+, Cl- cotransporter, I characterized the dystrophin deficient mouse after ischemic stroke. I found that dystrophin-deficient mice had a decrease in the formation of cerebral edema after transient brain ischemia when compared with strain-matched controls. Dystrophin-deficient mice had an increased mortality and seizure-like activity after transient brain ischemia. One hypothetical mechanism might be that increased plasma potassium is associated with a presumably decreased ability to buffer potassium after neuronal stimulation, due to its lack of aquaporin-4 and potassium channels (Kir4.1) at the end feet of astrocytes. Because of these additional effects, I concluded that the mdx mouse is not an ideal model for the study of a protective effect of an aquaporin-4 blocker after ischemic stroke.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectPhysiological Sciencesen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorYool, Andrea Jen_US
dc.contributor.advisorRitter, Leslie Sen_US
dc.contributor.chairYool, Andrea Jen_US
dc.contributor.chairRitter, Leslie Sen_US
dc.contributor.committeememberStamer, William D.en_US
dc.contributor.committeememberSherman, Scott J.en_US
dc.contributor.committeememberMcDonagh, Paul F.en_US
dc.identifier.proquest1840en_US
dc.identifier.oclc659746385en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.