Excitotoxicity, defined as cell death resulting from the toxic actions of excitatory amino acids, is actually considered as a major factor contributing to the early stage of ischemic cell death in stroke. In stroke, once vessel occlusion is produced, the disruptions to the blood flow in the affected areas decrease the delivery of oxygen and metabolic substrates to neurons. Consequently, the lack of oxygen interrupts oxidative phosphorylation by the mitochondria and drastically reduces cellular ATP production, which results in a rapid decline in cellular ATP. After several minutes, inhibition of the Na+/K+-ATPase function causes a profound loss of ionic gradients and depolarization of regulated neurons, which leads to excessive release of excitatory amino acids—particularly glutamate—to the extracellular compartment. The presence of excessive amounts of glutamate into the synapses and extrasynaptic sites can lead eventually to neuronal death. Excitotoxicity leads to a number of deleterious consequences, including impairment of cellular calcium homeostasis, generation of free radicals and oxidative stress, mitochondrial damage, and activation of several transcription factors and their genes expression. All these mechanisms’ acting synergy can cause neuron death by apoptosis. Oxidative stress induced by excitotoxicity is considered to be the main event leading to brain damage after stroke. On the basis of experimental models, there is ample evidence of the role of oxidative stress in ischemic brain damage.
Part of the book: Ischemic Stroke