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

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.