Delayed Neuronal Death in Ischemic Stroke: Molecular Pathways

IntroductionIschemic stroke is caused by a loss of blood flow and deficiency in glucose and oxygen to the brain.The lack of sufficient glucose and oxygen results in varying degrees of tissue damage and cell death following stroke.Reperfusion of blood flow after ischemia often compounds tissue damage that is sustained during the initial drop in local blood availability.The size and position of the affected region depends on which vessel is occluded.A complete loss of blood flow is rare, as rich networks of nearby blood vessels often compensate for reduced flow.The centre of the ischemic region, the core, is characterized by acute and mostly necrotic cell death resulting from severe anoxia and hypoglycemia.The region enveloping the core is known as the penumbra, which experiences a milder ischemic insult.The penumbra should be targeted for treatment strategies; it is usually much larger than the core and has a longer window of opportunity during which neurons can be prevented from dying.Many studies elucidate the molecular pathways of delayed neuronal death.This chapter presents the pathways and strategies that have been investigated to date. Events in strokeThere are major differences in the physiology and biochemistry of cell death between the core and penumbra, which suggests that different mechanisms of cell death are at work in these two regions. Core of ischemic infarctDuring a stroke, the ischemic core suffers a drop in energy.ATP levels in the core fall to a level only 15% of typical basal values within one or two minutes (Katsura et al., 1993;Lipton, 1999;Lipton & Whittingham, 1982;Martin et al., 1994) and do not recover by much after reperfusion (Sun et al., 1995).The core rapidly loses ion transporter functions and undergoes anoxic depolarization (Balestrino, 1995).Homeostasis of potassium, calcium, and sodium ions is lost (Harris & Symon, 1984).After reperfusion, extracellular K + typically returns to control levels for six hours and then stays slightly elevated above normal (Gido et al., 1997).There is some restoration of K + transporter functions, despite widespread cell www.intechopen.comAdvances in the Preclinical Study of Ischemic Stroke 118 injury and cell death within the core.Other responses to ischemia-induced energy loss include reduction or a complete halting of protein synthesis due to translation initiation factor (IF) inactivation (White et al., 2000) and insufficient GTP for ribosomal function.Permanent absence of protein synthesis continuing beyond reperfusion results in necrotic cell death.Recovery of protein synthesis is necessary for cell survival.Necrosis in the core is accompanied by glutamate release and excitotoxic cell damage to neighbouring regions. Penumbra of ischemic infarctBlood flow within the penumbra can vary substantially, subjecting cells to a wide range of stresses.Ischemic injury within the penumbra is variable in whether it results in cell death and in which molecular mechanisms are involved.Many of these mechanisms induce cell death in a delayed manner in neurons, which allows them to be saved if some neuroprotection is provided.This delay allows for therapeutic treatment, since the majority of stroke patients present many hours after suffering a stroke.Penumbral ischemia is milder than in the core; levels of ATP in the penumbra drop to an average of 50-70% of normal levels.Protein synthesis can be stalled following massive Ca 2+ influx, which can inactivate eIF-2a by preventing activation of eIF-2 and guanine nucleotide exchange factor during the initiation of translation (Kumar et al., 2001).Protein synthesis resumes after reperfusion and has a role in determining the extent of delayed neuronal death. ExcitotoxicityPenumbral cells are subject to excessive excitatory amino acid release from depolarized nearby cells in the ischemic core.Glutamate is the major excitatory neurotransmitter in the brain and the key mediator of intracellular communication, plasticity, growth and differentiation.The glutamate receptors implicated in excitotoxicity include the NMDA, AMPA, kainate, and other metabotropic glutamate receptors (Prass & Dirnagl, 1998).While present in synapses at micromolar concentrations, ischemia-induced depolarization causes a much larger release that triggers a chain reaction of depolarization and effects glutamate release in surrounding neurons (Paschen, 1996).The overstimulated neurons release Ca 2+ into their cytosol, halting protein synthesis and activating cyclooxygenase-2 (COX-2), increased nitric oxide (NO) production, phospholipases, calpains, cathepsins, and calcineurin (Ferrer, 2006;White et al., 2000).Degradation of calpain substrates such as spectrin and eIF4G then follows (White et al., 2000), while cathepsin activation may increase lysosomal activity and lead to autophagic cell death (Yamashima et al., 1998).Membranes are degraded by hyperactivated phospholipases, which produce free arachidonic acid that is metabolized during reperfusion to produce peroxidative derivatives that then act as free radicals.Excitotoxicity describes the damaging effects resulting from excessive excitatory neurotransmitter release.It is implicated in necrotic, apoptotic, and necroptotic cell death (Choi, 1996;Li et al., 2008). Oxidative stressOxidative damage by free radical generation mediates cell damage in ischemia (Gilgun-Sherki et al., 2002).It is involved in excitotoxicity, apoptosis, autophagic cell death, and inflammation.Penumbral free radical levels increase during early ischemia, remain www.intechopen.com

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