Models Of Preconditioning Crosstolerance

Numerous animal models have been described, in which brief episodes of global or focal ischemia are applied, followed by a more severe ischemic stress designed to kill neurons. In the classic experiment, brief global ischemia induced tolerance against subsequent global ischemia (3) in what is referred to as a global-global model of ischemic preconditioning. Subsequent studies have demonstrated that tolerance against focal ischemia can also be induced by brief focal ischemia (12), or focal-focal preconditioning. Furthermore, brief global ischemia has also been shown to reduce infarct size after focal ischemia induced by middle cerebral artery occlusion (global-focal) (13). Finally, transient focal ischemia increases tolerance against subsequent global ischemia. Interestingly, tolerance to ischemia in this focal-global paradigm develops in neurons within the region of focal ischemia (14) and in neurons outside the region of primary ischemia (15). Noxious stimuli other than ischemia can also confer tolerance to ischemia. For example, hyperthermia (16,17), as well as hypothermia (18), can protect from subsequent ischemia. Similarly, previous exposure to hypoxia reduces infarct after hypoxic/ischemic injury in neonatal rats (19), and hyperbaric oxygen can induce tolerance against focal ischemia (20). Other conditions and agents shown to induce ischemic tolerance in brain include spreading depression (21-23), status epilepticus (24), hypoglycemia (25), and low doses of the endotoxin lipopolysaccharide (LPS) (26-28). Finally, ischemic tolerance can be induced by chemical preconditioning, using substances that mimic the above-mentioned stimuli. The most extensively studied chemical preconditioning agent is 3-nitropropionic acid (3-NPA), an inhibitor of oxidative phosphorylation that binds to succinate dehydrogenase (SDH) and induces tolerance against in vitro ischemia in organotypic hippocampal slices (29), and in vivo ischemia in gerbils and rats ( 30-32 ).

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