Mechanisms of Protection in Ischemic Preconditioning

Organisms have developed complex endogenous defenses to counter environmental stress. The successful resistance to adversarial conditions, such as calorie or oxygen deprivation, has ensured that the strongest will survive. This lies at the root of preconditioning, that is, what is survived will strengthen; surviving mild forms of injury leads to tolerance of otherwise noxious injury. Preconditioning induces basic cellular survival mechanisms. Many different stimuli lead to preconditioning: drugs, ischemia, hypoxia, or hypothermia. In ischemic preconditioning exposing an organ to brief ischemia, induces temporary resistance to more severe ischemia, in the same or even a distant organ. The latter phenomenon is known as remote ischemic preconditioning. In this manner, for example, a limb is transiently made ischemic to protect the brain. Ischemic preconditioning has emerged as one of the most powerful anti-ischemic strategy in preclinical investigations. In laboratory models, protection through preconditioning has been consistently demonstrated across multiple organ systems and in many different animal species, leaving little doubt about the existence of this phenomenon. A recent literature search (Medline September 2012), combining the terms preconditioning and brain, lists >1000 citations. This large body of laboratory evidence supports investigating whether, and to what an extent, protection through preconditioning can be reproduced in humans. Proof of concept work is needed, and with that the question arises, which clinical setting may be most suitable for preliminary clinical trials. Preconditioning has been proposed as therapy for cerebral ischemia in several clinical settings of anticipated brain ischemia. These include carotid endarterectomy/stenting, coronary artery bypass graft surgery, and after subarachnoid hemorrhage (SAH). In the present review, we provide evidence that supports preconditioning for therapy of delayed cerebral ischemia (DCI) after SAH, arguing that proof of the ischemic preconditioning principle, may be most feasibly demonstrated in this setting.