Figure 1.

Overview of key events in the ischemic cascade: Ischemic stroke is caused by a sudden occlusion in the brain–blood supply. This results in irreversible damage of the neurons nearby the blood vessel, the ischemic core. This area is surrounded by the salvageable ischemic penumbra, in which neurons can be rescued if neuroprotective treatment is applied on time. In the core zone neurons, impaired oxygen and nutrient delivery results in a reduced ATP production, which will lead to loss of membrane potential and glutamate release. This will cause an ischemic cascade in neighboring neurons: the excess of glutamate will cause an increase in Na⁺ and Ca²⁺ influx, leading to cell swelling (edema) and depolarization, which will trigger K⁺ efflux and glutamate release. In addition, the increase in intracellular Ca²⁺ will also lead to mitochondrial damage as well as ROS and NO formation, both events causing mitochondrial damage and, thus, apoptosis and necrosis. This increased oxidative stress as well as the necrotic/apoptotic events lead to the secretion of inflammatory mediators, which exacerbate a negative effect of microglial activation and infiltration of native immune cells, such as neutrophils and macrophages [25,26]. Figure created with biorender.com (accessed on 1 May 2021).