Drowning stars: reassessing the role of astrocytes in brain edema

Abstract

Edema formation frequently complicates brain infarction, tumors, and trauma. Despite the significant mortality of this condition, current treatment options are often ineffective or incompletely understood. Recent studies have revealed the existence of a brain-wide paravascular pathway for cerebrospinal (CSF) and interstitial fluid (ISF) exchange. The current review critically examines the contribution of this 'glymphatic' system to the main types of brain edema. We propose that in cytotoxic edema, energy depletion enhances glymphatic CSF influx, whilst suppressing ISF efflux. We also argue that paravascular inflammation or 'paravasculitis' plays a critical role in vasogenic edema. Finally, recent advances in diagnostic imaging of glymphatic function may hold the key to defining the edema profile of individual patients, and thus enable more targeted therapy.

Keywords: aquaporin-4; astrocyte; cerebral edema; glymphatic; paravascular.

Figure 1

The glymphatic system regulates cerebrospinal and interstitial fluid exchange in the brain. (A) Illustration of the main fluid compartments in the brain. (B) Diagram of fluid influx via penetrating arteries and efflux along a subset of large-caliber veins. (C) Diagram of proposed molecular mechanisms governing paravascular CSF-ISF exchange. Abbreviations: Paravascular space (PVS), solute carrier (SLC), zonula occludens (ZO), connexin (CNX) and Na⁺-K⁺-ATPase (NKA).

Figure 2

Focal brain edema is caused by the interplay of cytotoxic changes in the core of an infarct or injury, and ionic mechanisms in the surrounding tissue or penumbra. (A) Illustration of focal brain edema following an ischemic stroke. (B) Diagram showing how net influx of Na⁺ into dead or dying cells in the core can set up an ionic gradient for water influx into the penumbra, which is incompletely counterbalanced by K⁺ efflux. Abbreviations: Plasma membrane (P.m.), end-foot membrane (E.f.m.).

Figure 3

Phases of brain edema formation and resorption after an acute ischemic stroke. (A) Graph showing the likely changes in key parameters such as blood flow and water content after an acute infarct. (B) Diagram of suggested mechanisms that might be involved during the different phases of brain edema.