The role of aquaporin-4 in cerebral water transport and edema

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✓Despite decades of research into the pathogenesis of cerebral edema, nonsurgical therapy for brain swelling has advanced very little after more than half a century. Recent advancements in our understanding of molecular water transport have generated interest in new targets for edema therapy. Aquaporin-4 (AQP4) is the primary cellular water channel in the brain, localized to astrocytic foot processes along the blood–brain barrier and brain–cerebrospinal fluid interface. Multiple studies of transgenic mice with a complete deficiency or altered expression of AQP4 suggest a prominent role for AQP4 in cerebral water transport. In models of cellular (cytotoxic) edema, AQP4 deletion or alteration has been shown to be protective, reducing edema burden and improving overall survival. In contrast, AQP4 deletion in extra-cellular (vasogenic) edema results in decreased edema clearance and greater progression of disease. The data strongly support the conclusion that AQP4 plays a pivotal role in cerebral water transport and is an essential mediator in the formation and resorption of edema fluid from the brain parenchyma. These findings also suggest that drug therapy targeting AQP4 function and expression may dramatically alter our ability to treat cerebral edema.

Abbreviations used in this paper:AQP = aquaporin; BBB = blood–brain-barrier; CSF = cerebrospinal fluid; ICP = intracranial pressure; MCA = middle cerebral artery.

✓Despite decades of research into the pathogenesis of cerebral edema, nonsurgical therapy for brain swelling has advanced very little after more than half a century. Recent advancements in our understanding of molecular water transport have generated interest in new targets for edema therapy. Aquaporin-4 (AQP4) is the primary cellular water channel in the brain, localized to astrocytic foot processes along the blood–brain barrier and brain–cerebrospinal fluid interface. Multiple studies of transgenic mice with a complete deficiency or altered expression of AQP4 suggest a prominent role for AQP4 in cerebral water transport. In models of cellular (cytotoxic) edema, AQP4 deletion or alteration has been shown to be protective, reducing edema burden and improving overall survival. In contrast, AQP4 deletion in extra-cellular (vasogenic) edema results in decreased edema clearance and greater progression of disease. The data strongly support the conclusion that AQP4 plays a pivotal role in cerebral water transport and is an essential mediator in the formation and resorption of edema fluid from the brain parenchyma. These findings also suggest that drug therapy targeting AQP4 function and expression may dramatically alter our ability to treat cerebral edema.

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Address reprint requests to: Geoffrey T. Manley, M.D., Ph.D., 1001 Potrero Avenue, Room 101, San Francisco, California 94110. email: manley@itsa.ucsf.edu.

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