3.2.2. Astrocytes

Similar to microglia, astrocytes are housekeeping cells essential to the continuous functioning of the central nervous system. Astrocytes are involved in the physiological and pathological functioning of the brain. They regulate the water–ion balance; secrete neurotrophic factors; and remove unnecessary neurotransmitters, transport products, and waste of cellular metabolism. Astrocytes participate in the structure and function of the blood–brain barrier [59]. Under normal conditions, astrocytes take up excess glutamate from the extracellular space and convert it into glutamine for neurons to reuse, but during brain damage following ischemia, the degree of astrocyte damage affects their glutamateuptake capacity [1,34,59]. How ischemia affects glutamate uptake by astrocytes is not fully elucidated, but expression of the excitatory amino acid transporter 2 (EAAT2) has been suggested to be impaired post-ischemia [60,61].

Cytokines from neurons and neuroglial cells cause post-ischemic astrocyte hyperplasia. As a result of ischemia, astrocytes release vimentin, nestin, IL-1β, monocyte chemotactic protein-1, and glial fibrillary acidic protein [27,62], which contribute to the development of reactive gliosis and the formation of glial scars after ischemia [27,63]. As a result of the Na+/K+ pump dysfunction, astrocytes swell after brain ischemia [62,64,65], which causes an increase in intracranial pressure and a consequent reduction in cerebral blood flow. Activated astrocytes release matrix metalloproteinase-2 (MMP-2) capable of damaging the extracellular matrix [66] and also contribute to the presence of ephrin-A5 in the ischemic brain area, which hinders axonal sprouting [67]. After embolic focal ischemia of the brain in rats, an exaggerated astroglial response is observed in the ischemic injury core from 4 h to 1 day, it peaks on day 4, persists for 28 days, and forms a glial scar [68]. Three days after reversible total brain ischemia in hippocampus astrocytes, significant upregulation of iNOS, glial fibrillary acidic protein (GFAP), and NADPH diaphorease expression was observed [69]. Post-mortem examination of the brain tissue after ischemia of patients who died within 7 days post-stroke showed increased expression of IL-15 in astrocytes [1]. Alternatively, IL-15 knockdown in astrocytes reduced ischemic brain damage in mice after transient local ischemia [70]. Transgenic mice expressing IL-15 with the controlled GFAP promoter exhibited increased cerebral infarction and increased neurological deficits following cerebral ischemia [1]. In addition, GFAP/Vimentin double-knockout mice showed reduced cortical blood flow in the brain and greater lesions following local ischemia [71]. Astrocytes release fibroblast growth factor-2, brain-derived neurotrophic factor, and nerve growth factor, which have neuroprotective properties [71,72]. In addition to their neurotrophic support, structurally, astrocytes by their terminal feet have a strong relationship with the endothelial cells of the brain's capillaries and the pericytes that make up the blood–brain barrier. During brain ischemia, MMP-9 breaks the connection between the terminal feet of astrocytes and endothelial cells by degrading the basal lamina [73]. Consequently, the open blood–brain barrier acts as the main gateway for invasion of the brain by peripheral inflammatory cells.
