Mechanisms of Astrocyte-Mediated Cerebral Edema

Abstract

Cerebral edema formation stems from disruption of blood brain barrier (BBB) integrity and occurs after injury to the CNS. Due to the restrictive skull, relatively small increases in brain volume can translate into impaired tissue perfusion and brain herniation. In excess, cerebral edema can be gravely harmful. Astrocytes are key participants in cerebral edema by virtue of their relationship with the cerebral vasculature, their unique compliment of solute and water transport proteins, and their general role in brain volume homeostasis. Following the discovery of aquaporins, passive conduits of water flow, aquaporin 4 (AQP4) was identified as the predominant astrocyte water channel. Normally, AQP4 is highly enriched at perivascular endfeet, the outermost layer of the BBB, whereas after injury, AQP4 expression disseminates to the entire astrocytic plasmalemma, a phenomenon termed dysregulation. Arguably, the most important role of AQP4 is to rapidly neutralize osmotic gradients generated by ionic transporters. In pathological conditions, AQP4 is believed to be intimately involved in the formation and clearance of cerebral edema. In this review, we discuss aquaporin function and localization in the BBB during health and injury, and we examine post-injury ionic events that modulate AQP4- dependent edema formation.

Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema

“…20 Aquaporins-mainly aquaporin4-are expressed in astrocytes; however, the regulation of aquaporin 4, and its contribution (if any) to PHO, remains to be determined. 21,22 In ischaemic stroke and other acute CNS patholo gies, the Na-K-Cl symporter (NKCC1) and the SUR1-TRPM4 (sulphonylurea receptor 1-transient receptor potential cation channel subfamily M member 4) channel (formerly known as the SUR1regulated NC CaATP channel) are involved in ionic oedema. 10,11,23 The poten tial activation of both of these transporters in response to the effects of ICH suggests a role in PHO that is yet to be clearly demonstrated (Figure 2).…”

Drowning stars: reassessing the role of astrocytes in brain edema

“…Unfortunately, no studies have directly examined penumbral ISF volume in vivo during brain edema to help us resolve this important point. A more detailed discussion of astrocyte volume regulation is beyond the remit of the current review we refer the reader to other overview articles on this topic [3, 8, 81]. …”

Assessing Blood Brain Barrier Permeability in Traumatic Brain Injury Research

“…These endothelial cells are further covered by astrocyte end processes and have basal lamina shared with luminal pericytes. Astrocytes express high levels of aquaporin-4, a water channel protein that is known to be involved in the clearance of edema [10,11].…”

“…The first strategy is using brain water content, the simplest method of indirectly assessing the degree of BBB dysfunction and offers global differences between treatments, but is subject to variations in animal sacrifice technique and post mortem handling of brain tissues [15]. The second strategy is to measure the components involved in forming the BBB, such as perivascular astrocytes, tight junction proteins such as claudin-5, occludin and zona occludens-1, as well as the components responsible for maintaining and restoring water hemostasis, such as aquaporin-4 [10,16,17]. While this strategy can describe how individual components of the BBB change following injury and treatment, the effect of other components and the function of the BBB cannot be directly assessed.…”