Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke.

Adjanie Patabendige,Jon Sen,Stuart Jenkins,Ruoli Chen,Ayesha Singh

doi:10.3390/ijms22084280

Abstract

Transient or permanent loss of tissue perfusion due to ischaemic stroke can lead to damage to the neurovasculature, and disrupt brain homeostasis, causing long-term motor and cognitive deficits. Despite promising pre-clinical studies, clinically approved neuroprotective therapies are lacking. Most studies have focused on neurons while ignoring the important roles of other cells of the neurovascular unit, such as astrocytes and pericytes. Astrocytes are important for the development and maintenance of the blood–brain barrier, brain homeostasis, structural support, control of cerebral blood flow and secretion of neuroprotective factors. Emerging data suggest that astrocyte activation exerts both beneficial and detrimental effects following ischaemic stroke. Activated astrocytes provide neuroprotection and contribute to neurorestoration, but also secrete inflammatory modulators, leading to aggravation of the ischaemic lesion. Astrocytes are more resistant than other cell types to stroke pathology, and exert a regulative effect in response to ischaemia. These roles of astrocytes following ischaemic stroke remain incompletely understood, though they represent an appealing target for neurovascular protection following stroke. In this review, we summarise the astrocytic contributions to neurovascular damage and repair following ischaemic stroke, and explore mechanisms of neuroprotection that promote revascularisation and neurorestoration, which may be targeted for developing novel therapies for ischaemic stroke.

Highlights

Stroke is a leading cause of death and disability, causing over 5.5 million deaths in 2016 [1]
Dhandapani et al [179] reported that soluble factors in astrocyte-conditioned medium (ACM) protect murine neurons from serum-deprivation induced cell death by releasing transforming growth factor β (TGF-β), which activates the activator protein-1 (AP-1) protective pathway and prevents apoptosis
Astrocytes are critical for BBB reconstruction and neuroprotection in the acute stages of ischaemic stroke, as they increase the uptake of extracellular glutamate and sodium/potassiumATPase activity

Summary

Introduction

Stroke is a leading cause of death and disability, causing over 5.5 million deaths in 2016 [1]. Glial cells have important roles in brain homeostasis as well as in the development and maintenance of the blood–brain barrier (BBB) [17] They can have either protective or detrimental effects on neurons following ischaemic stroke [18,19,20,21,22,23,24]. Astrocytes fulfil many important roles in both healthy and injured brains (Figure 1) These include maintaining ion and pH homeostasis in the CNS; promoting the synthesis and removal of neurotransmitters; providing glucose supply and antioxidant defence; regulating synaptic activity by producing various cytokines, chemokines, growth factors and metabolites; supporting neurons; regulating cerebral blood flow (CBF); and supporting BBB formation and function [25]. Inhibiting changes in AQP4 localisation might be a better therapeutic strategy than complete blocking of AQP4, which has an important role in brain fluid homeostasis

The Role of Astrocyte Activation in Neuroinflammation after Ischaemic Stroke

Astrocyte Activation and Glial Scar Formation

The Role of Astrocyte Secretions in Ischaemic Stroke

Targeting Astrocytes as a New Therapy for Stroke

Findings

Conclusions