Excitotoxicity and Oxidative Stress in Acute Stroke

Abstract

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.

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…This mostly linear relay of cellular events starts with a low supply of oxygen and glucose, while oxygen insufficiency completely disrupts mitochondrial oxidative phosphorylation (Erecińska and Silver, 2001). As most of the energy formed in the brain is due to glucose oxidation to carbon dioxide and water (Rama and García, 2016), its absence causes ATP depletion within only a few minutes, which is the result of no long-term energy stores in the brain (Doyle et al, 2008). The lack of ATP hampers the physiological function of ion pumps and, as the cells fail to maintain electrochemical gradients, it results in depolarization due to the aberrant influx of sodium ions (Na + ) and Ca 2+ into the cell, accompanied by potassium ion (K + ) efflux.…”

“…Such excessive [Ca 2+ ] i initiates a series of molecular neurotoxic cascades, including the activation and overstimulation of proteases, lipases, phosphatases, and endonucleases (Orrenius et al, 2003). This leads to the activation of several signaling pathways, mainly causing an overproduction of free radicals, mitochondrial damage, cell membrane disruption, and DNA fragmentation, which all culminate in apoptotic or necrotic cell death (Figure 2; Rama and García, 2016).…”

“…The ischemia-induced excitotoxicity results in mitochondrial malfunctioning due to the damage to mitochondrial proteins, membranes, and DNA, thus impairing the ability of mitochondria to synthesize ATP and carry out their wide range of metabolic functions (Rama and García, 2016). The permeability transition pore (mPTP) in the mitochondrial membrane develops in response to Ca 2+ overload and enables the release of pro-apoptotic factors.…”

“…Necrosis occurs mainly in the ischemic core as a result of a severe deficit or absence of oxygen and glucose. On the contrary, apoptosis takes place in the ischemic penumbra, where certain levels of oxygen and glucose remain, still maintaining the functional activity of cells (Rama and García, 2016). The difference is also in the time window when these mechanisms occur.…”

Available Therapeutics after a Stroke: Current and Promising Options

“…Alternatively, under ischemic conditions, reperfusion provides sufficient substrate for different enzymatic oxidation reactions to take place, causing an overproduction of free oxygen radicals (ROS) and the inactivation of antioxidant enzymes [20]. Concurrently, nitric oxide (NO) increases due to the activation of endothelial and neuronal nitric oxide synthases as a result of increased Ca 2+ concentration, NO reacts with ROS and forms a highly toxic peroxynitric acid (ONOOH) [21].…”