Mechanisms of Ischemic Cell Death

Ischemic stroke compromises blood flow and energy supply to the brain, which triggers at least five fundamental mechanisms that lead to cell death: excito-toxicity and ionic imbalance, oxidative/nitrative stress, inflammation, apoptosis, and peri-infarct depolarization (Fig. 1.1). These pathophysiological processes evolve in a series of complex spatial and temporal events spread out over hours or even days

Figure 1.1

Major pathways implicated in ischemic cell death: excitotoxicity, ionic imbalance, oxidative and nitrative stresses, and apoptotic-like mechanisms.There is extensive interaction and overlap between multiple mediators of cell injury and cell death. After ischemic onset, loss of energy substrates leads to mitochondrial dysfunction and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Additionally, energy deficits lead to ionic imbalance, and exci-totoxic glutamate efflux and build up of intracellular calcium. Downstream pathways ultimately include direct free radical damage to membrane lipids,cellular proteins,and DNA,as well as calcium-activated proteases,plus caspase cascades that dismantle a wide range of homeostatic, reparative, and cytoskeletal proteins. (From Lo et al., Nat Rev Neurosci 2003, 4:399-415)

Fig. 1.2

Putative cascade of damaging events in focal cerebral ischemia. Very early after the onset of the focal perfusion deficit, excitotoxic mechanisms can damage neurons and glia lethally.In addition, excitotoxicity triggers a number of events that can further contribute to the demise of the tissue. Such events include peri-infarct depolarizations and the more-delayed mechanisms of inflammation and programmed cell death. The x-axis reflects the evolution of the cascade over time, while the y-axis aims to illustrate the impact of each element of the cascade on the final outcome. (From Dirnagel et al., Trends Neurosci 1999; 22:391-397)

(Fig. 1.2), have overlapping and redundant features, and mediate injury within neurons, glial cells, and vascular elements [1]. The relative contribution of each process to the net stroke-related injury is graphically depicted in Fig. 1.2. Within areas of severely reduced blood flow - the "core" of the ischemic territory - excitotoxic and necrotic cell death occurs within minutes, and tissue undergoes irreversible damage in the absence of prompt and adequate reperfusion. However, cells in the peripheral zones are supported by collateral circulation, and their fate is determined by several factors including the degree of ischemia and timing of reperfusion. In this peripheral region, termed the "ischemic penumbra," cell death occurs relatively slowly via the active cell death mechanisms noted above; targeting these mechanisms provides promising therapeutic opportunities.

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