Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema.

Ischemic stroke, a major cause of mortality, is frequently accompanied by life-threatening cerebral edema. Aquaporin-4 (Aqp4), an astrocytic transmembrane water channel, is an important molecular contributor to cerebral edema formation. Past studies of Aqp4 expression and localization after ischemia examined grey matter exclusively. However, as white matter astrocytes differ developmentally, physiologically, and molecularly from grey matter astrocytes, we hypothesized that functionally important regional heterogeneity exists in Aqp4 expression and subcellular localization following cerebral ischemia. Subcellular localization of Aqp4 was compared between cortical and white matter astrocytes in postmortem specimens of patients with focal ischemic stroke versus controls. Subcellular localization and expression of Aqp4 was examined in rats subjected to experimental stroke. Volumetric analysis was performed on the cortex and white matter of rats subjected to experimental stroke. Following cerebral ischemia, cortical astrocytes exhibited reduced perivascular Aqp4 and unchanged Aqp4 protein abundance. In contrast, white matter astrocytes exhibited increased perivascular and plasmalemmal Aqp4 and a 2.2- to 6.2-fold increase in Aqp4 isoform abundance. Ischemic white matter swelled by approximately 40 %, while cortex swelled by approximately 9 %. The findings reported here raise the possibility that cerebral white matter may play a heretofore underappreciated role in the formation of cerebral edema following ischemia.

Hemorrhage in the central nervous system (CNS), including intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and aneurysmal subarachnoid hemorrhage (aSAH), remains highly morbid. Trials of medical management for these conditions over recent decades have been largely unsuccessful in improving outcome and reducing mortality. Beyond its role in creating mass effect, the presence of extravasated blood in patients with CNS hemorrhage is generally overlooked. Since trials of surgical intervention to remove CNS hemorrhage have been generally unsuccessful, the potent neurotoxicity of blood is generally viewed as a basic scientific curiosity rather than a clinically meaningful factor. In this review, we evaluate the direct role of blood as a neurotoxin and its subsequent clinical relevance. We first describe the molecular mechanisms of blood neurotoxicity. We then evaluate the clinical literature that directly relates to the evacuation of CNS hemorrhage. We posit that the efficacy of clot removal is a critical factor in outcome following surgical intervention. Future interventions for CNS hemorrhage should be guided by the principle that blood is exquisitely toxic to the brain.

Brain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain’s capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na ⁺ /Ca ²⁺ exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na ⁺ through SUR1-TRPM4 induced Ca ²⁺ transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca ²⁺ . This increase in Ca ²⁺ stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce postischemic brain swelling in stroke patients.

The perivascular astrocyte endfoot is a specialized and diffusion-limited subcellular compartment that fully ensheathes the cerebral vasculature. Despite their ubiquitous presence, a detailed understanding of endfoot physiology remains elusive, in part due to a limited understanding of the proteins that distinguish the endfoot from the greater astrocyte body. Here, we developed a technique to isolate astrocyte endfeet from brain tissue, which was used to study the endfoot proteome in comparison to the astrocyte somata. In our approach, brain microvessels, which retain their endfoot processes, were isolated from mouse brain and dissociated, whereupon endfeet were recovered using an antibody-based column astrocyte isolation kit. Our findings expand the known set of proteins enriched at the endfoot from 10 to 516, which comprised more than 1/5th of the entire detected astrocyte proteome. Numerous critical electron transport chain proteins were expressed only at the endfeet, while enzymes involved in glycogen storage were distributed to the somata, indicating subcellular metabolic compartmentalization. The endfoot proteome also included numerous proteins that, while known to have important contributions to blood-brain barrier function, were not previously known to localize to the endfoot. Our findings highlight the importance of the endfoot and suggest new routes of investigation into endfoot function.