Cerebral edema is characterized by the pathological swelling of brain tissue due to progressive increase in brain water content. It is a frequent and feared clinical complication that develops in a broad range of cerebral insults such as ischemia (Ribeiro Mde et al. 2006
), trauma (Zador et al. 2007
), tumors (Saadoun et al. 2002
) and inflammation (Papadopoulos and Verkman 2005
). The rigid cranium opposes the progressive swelling of brain tissue, leading to elevated intracranial pressure, decreased cerebral blood flow, and ultimately cerebral herniation and death. Klatzo broadly categorized the mechanisms of brain tissue swelling as cytotoxic edema and vasogenic edema in 1967 (Klatzo 1967
). The former process involves progressive cell swelling due to rapid water uptake, whereas in the case of vasogenic edema water leaks into the extracellular space due to defects in the blood–brain barrier. Although these two mechanisms coexist in most brain pathologies, instead of a pure cytotoxic edema or vasogenic edema, there is typically an appreciable dominance of one type over the other in each disease. For example, vasogenic edema seems to dominate in tumors and cerebral abscesses, while cytotoxic edema develops in ischemic stroke and brain trauma.
Cytotoxic edema is a significant clinical problem that can develop in response to a large (“malignant”) middle cerebral artery (MCA) occlusion (Hacke et al. 1996
; Bardutzky and Schwab 2007
) and has been associated with approximately 80% mortality rate. Cerebral vascular occlusion initiates a sequence of events involving cell swelling, followed by BBB leakage and hemorrhagic conversion of the tissue (Simard et al. 2007
). The strategy for the treatment of cerebral edema associated with these large ischemic strokes is limited to the use of intravascular administration of hyperosmolar solutions to remove the excess water from the brain, or removal of a large bone flap to allow the brain to swell outside the rigid cranium (decompressive craniectomy). These methods have remained unchanged for the past 90 years. More recently, the discovery of aquaporin membrane water channels has provided new insights into the molecular mechanisms of edema formation and brain water transport.
The glial membrane water channel aquaporin-4 (AQP4) is largely expressed in astrocytic processes adjacent to cerebral capillaries and pial membranes lining the subarachnoid space (). Such strategic localization at these tissue-water interfaces, and the high water permeability of the channel, makes AQP4 an important route for transporting water to and from the brain. A large body of evidence from transgenic mice deficient in AQP4 has demonstrated the role of this water channel in cytotoxic and vasogenic edema. These findings suggest AQP4 is a potential therapeutic target in the treatment of cerebral edema developing in response to various CNS pathologies including stroke.
Fig. 1 (a, b) Diagram depicts the structure of an AQP monomer and its clustering into tetramers. (a) Schematic demonstration of the transmembrane α-helices of AQP4 numbered from 1–6, which surround the highly selective water pore. The highly (more ...)