Consequences of Excitotoxicity and Calcium Overload

Calcium is known to activate a variety of processes, ultimately leading to ischemic cell death (12). In the setting of ischemia, excess intracellular calcium leads to overactivation of a variety of enzyme systems (lipases, endonucleases, and other proteases) and to formation of ROS or NO, both of which lead to cell death. Calpain, a calcium-activated cysteine protease, can degrade several structural proteins. Pharmacologic inhibitors have been shown to limit injury in several cerebral ischemia models, indicating that calpain might represent an important therapeutic target (27) . Calcium also activates phospholipase A2 (PLA2) and hydrolyzes glycerophospho-lipids to release free fatty acids and lysophospholipids. Membrane-bound PLA) activity is increased following glutamate exposure. PLA2 is a key enzyme involved in membrane remodeling, inflammation, and lipid metabolism. The primary substrate for these enzymes is glyc-erophospholipid, a major constituent of the cell membrane. Following ischemia, PLA2 not only directly damages cell membranes but also activates arachidonic acid and other cell-death pathways (28). Arachidonic acid metabolism then leads to the generation of ROS and subsequent lipid peroxidation. Additionally, calcium can activate xanthine oxidase, which results in the generation of superoxide.

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