A review of progress in understanding the pathophysiology and treatment of brain edema

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.

Brain edema leading to an expansion of brain volume has a crucial impact on morbidity and mortality following traumatic brain injury (TBI) as it increases intracranial pressure, impairs cerebral perfusion and oxygenation, and contributes to additional ischemic injuries. Classically, two major types of traumatic brain edema exist: "vasogenic" due to blood-brain barrier (BBB) disruption resulting in extracellular water accumulation and "cytotoxic/cellular" due to sustained intracellular water collection. A third type, "osmotic" brain edema is caused by osmotic imbalances between blood and tissue. Rarely after TBI do we encounter a "hydrocephalic edema/interstitial" brain edema related to an obstruction of cerebrospinal fluid outflow. Following TBI, various mediators are released which enhance vasogenic and/or cytotoxic brain edema. These include glutamate, lactate, H(+), K(+), Ca(2+), nitric oxide, arachidonic acid and its metabolites, free oxygen radicals, histamine, and kinins. Thus, avoiding cerebral anaerobic metabolism and acidosis is beneficial to control lactate and H(+), but no compound inhibiting mediators/mediator channels showed beneficial results in conducted clinical trials, despite successful experimental studies. Hence, anti-edematous therapy in TBI patients is still symptomatic and rather non-specific (e.g. mannitol infusion, controlled hyperventilation). For many years, vasogenic brain edema was accepted as the prevalent edema type following TBI. The development of mechanical TBI models ("weight drop," "fluid percussion injury," and "controlled cortical impact injury") and the use of magnetic resonance imaging, however, revealed that "cytotoxic" edema is of decisive pathophysiological importance following TBI as it develops early and persists while BBB integrity is gradually restored. These findings suggest that cytotoxic and vasogenic brain edema are two entities which can be targeted simultaneously or according to their temporal prevalence.

The water channel AQP4 is concentrated in perivascular and subpial membrane domains of brain astrocytes. These membranes form the interface between the neuropil and extracerebral liquid spaces. AQP4 is anchored at these membranes by its carboxyl terminus to alpha-syntrophin, an adapter protein associated with dystrophin. To test functions of the perivascular AQP4 pool, we studied mice homozygous for targeted disruption of the gene encoding alpha-syntrophin (alpha-Syn(-/-)). These animals show a marked loss of AQP4 from perivascular and subpial membranes but no decrease in other membrane domains, as judged by quantitative immunogold electron microscopy. In the basal state, perivascular and subpial astroglial end-feet were swollen in brains of alpha-Syn(-/-) mice compared to WT mice, suggesting reduced clearance of water generated by brain metabolism. When stressed by transient cerebral ischemia, brain edema was attenuated in alpha-Syn(-/-) mice, indicative of reduced water influx. Surprisingly, AQP4 was strongly reduced but alpha-syntrophin was retained in perivascular astroglial end-feet in WT mice examined 23 h after transient cerebral ischemia. Thus alpha-syntrophin-dependent anchoring of AQP4 is sensitive to ischemia, and loss of AQP4 from this site may retard the dissipation of postischemic brain edema. These studies identify a specific, syntrophin-dependent AQP4 pool that is expressed at distinct membrane domains and which mediates bidirectional transport of water across the brain-blood interface. The anchoring of AQP4 to alpha-syntrophin may be a target for treatment of brain edema, but therapeutic manipulations of AQP4 must consider the bidirectional water flux through this molecule.