Fig. 1.

Summary of pathophysiological processes developing in the course of ischemic stroke. The consequences of ischemic stroke result from processes beginning in a strictly defined time sequence. A decrease in cerebral blood flow results in reduction of oxygen and glucose delivered to the brain tissue. This initiates a cascade of biochemical processes ultimately leading to cellular destruction and death. One of the earliest consequences of these processes is change of oxidative glycolysis into less effective anaerobic pathway, followed by decrease in ATP production and raising lactate concentration. This results in decrease in all energy-dependent metabolic processes and dysfunction of the ion pumps leading to changes of ion concentrations (i.e., decrease in K⁺ intracellular levels and increase in Cl⁻, Na⁺, and Ca²⁺ levels). This in turn contributes to influx of water and development of brain swelling. Depolarization of neuronal cell membranes leads to release of excessive amounts of glutamate and triggering glutamatergic excitotoxicity. Stimulating effect of glutamate, by changing Ca²⁺ concentration and activation of enzymes (e.g., proteases, lipases, phosphatases, and endonucleases), leads to further cell destruction. This is accompanied by the activation of oxidative stress along with an increase in production of free oxygen and nitrogen radicals. A further consequence of these processes is triggering of inflammatory response and release of proinflammatory cytokines and chemokines which destructive action affects all elements of neurovascular unit (NVU). In cerebral vessels, increase in permeability of BBB and damage to the endothelial cells occur, accompanied by up-regulation of thrombotic mechanisms. These processes are accompanied by apoptotic and necrotic cell death, which are dependent on the length of cerebral blood flow reduction, extent of the energetic metabolism disturbances, and localization of the cells (within infarct core or penumbra). Decrease in the cerebral blood flow and reduced availability of oxygen and glucose initiate the acute phase (up to 24 h from ischemia onset) processes in the course of ischemic stroke, i.e., glutamatergic excitotoxicity, increase in Ca²⁺ levels, and anaerobic glycolysis, leading to reduced efficiency of the energetic metabolism. The subacute phase (up to 7 days from ischemia onset) is characterized by occurrence of various forms of cell death, the blood–brain barrier (BBB) disintegration and leakage, as well as, initiation of the inflammatory response followed by release of mediators exacerbating the effects of primary damage. In contrast to the earlier phases, during the late phase (starting one week from ischemia onset), the initiated processes lead to limiting of deleterious effects of the cerebral blood flow reduction through development of reactive gliosis and gliotic scar, which enables demarcation of the necrotic infarct core from the surrounding intact tissue. At this phase, the reparative processes resulting from cell proliferation and differentiation dominate, what is reflected in intensive reconstruction of the cellular populations, angiogenesis and re-myelination.