Conclusions And Future Directions

The events that lead to neuronal death after global cerebral ischemia and reperfusion are multifac-torial and interrelated in a complex fashion. Many agents have been described as neuroprotectants in experimental stroke models, but fewer agents have been documented as neuroprotectants in global cerebral ischemia models. Experimental stroke models have a gradient of CBF reduction, permitting salvage of tissue, in which metabolism is only partially compromised. With uniformly severe reductions in CBF in most global ischemia models, the mechanisms of cell death are mul-tifactorial, and manipulation of a single pathway is less likely to have a significant impact on cell survival. When an improvement in outcome can be demonstrated with a particular agent, the duration of global ischemia is typically constrained to 5 to 12 min, and efficacy may be limited to delayed neurodegeneration in hippocampus. The use of multiple agents in a "cocktail" regimen, targeting reactive oxygen species, ER stress, multiple pathways of regulated cell death signaling, and inflammatory mediators, is more likely to be required for obtaining clinically significant improvements from global ischemia, particularly for long ischemic durations. Postresuscitation hypothermia, which is one of the few therapies found to be efficacious clinically after cardiac arrest, acts to limit injury via multiple mechanisms and may be viewed as a "broad-spectrum" neuroprotectant. However, the logistic constraints of rapidly reducing brain temperature in humans during early reperfusion after cardiac arrest, particularly out-of-hospital arrests, will require the continued search for neuroprotectants that (i) can be administered early to limit the initial injury and extend the therapeutic window for hypothermia and (i i) can complement the efficacy of agents targeted at delayed mechanisms of injury that involve apoptosis and inflammation. As in the field of focal ischemic research, future work on global ischemic injury is expected to expand into cell engineering strategies for regenerating selectively vulnerable neurons.

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