Central Role of Maladapted Astrocytic Plasticity in Ischemic Brain Edema Formation

Abstract

Brain edema formation and the ensuing brain damages are the major cause of high mortality and long term disability following the occurrence of ischemic stroke. In this process, oxygen and glucose deprivation and the resulting reperfusion injury play primary roles. In response to the ischemic insult, the neurovascular unit experiences both intracellular and extracellular edemas, associated with maladapted astrocytic plasticity. The astrocytic plasticity includes both morphological and functional plasticity. The former involves a reactive gliosis and the subsequent glial retraction. It relates to the capacity of astrocytes to buffer changes in extracellular chemical levels, particularly K(+) and glutamate, as well as the integrity of the blood-brain barrier (BBB). The latter involves the expression and activity of a series of ion and water transport proteins. These molecules are grouped together around glial fibrillary acidic protein (GFAP) and water channel protein aquaporin 4 (AQP4) to form functional networks, regulate hydromineral balance across cell membranes and maintain the integrity of the BBB. Intense ischemic challenges can disrupt these capacities of astrocytes and result in their maladaptation. The maladapted astrocytic plasticity in ischemic stroke cannot only disrupt the hydromineral homeostasis across astrocyte membrane and the BBB, but also leads to disorders of the whole neurovascular unit. This review focuses on how the maladapted astrocytic plasticity in ischemic stroke plays the central role in the brain edema formation.

Keywords: aquaporin-4; astrocytes; brain edema formation; functional plasticity; glial fibrillary acidic protein; hydromineral balance; ischemic stroke; morphological plasticity.

Figure 1

Diagrammatic drawing of the spatiotemporal features of astrocytic plasticity in ischemic stroke (A–C). Spatiotemporal features of astrocytic involvement in ischemic stroke in the early stage (0–24 h) of a mild stroke (A), middle stage (>24–72 h, B) and the late stage (C), respectively. The abbreviations are, Glu, glutamate; RVD, regulatory volume decrease.

Figure 2

Diagrammatic drawing of the astrocytic functional plasticity in ischemic stroke (A–C). The functional plasticity at different loci relative to the infarct core: normally irrigated tissues (A), the penumbra (B) and the lesion core (C), respectively. The abbreviations are, AQP4, Aquaporin-4; GFAP, glial fibrillary acidic protein; GLT-1, glutamate transporter-1; Kir4.1, inward rectifier K⁺ channel 4.1; NKCC1, Na⁺, K⁺, 2Cl⁻ and water co-transporter. Others refer to Figure 1.