Ischemic preconditioning in the brain.

physiologic responses to its environment is important for survival. Certain organs respond to sub-lethal exposures to hypoxia or ischemia by a variety of physiologic mechanisms. Some of these mechanisms induce a greater tolerance to a subsequent exposure to hypoxia or ischemia. This phenomenon is described as ischemic or hypoxic preconditioning.1,2 It is nature’s “what doesn’t kill you makes you stronger” message. There are a number of important biological implications of this phenomenon. First, potential therapeutic benefits of preconditioning may be recruited when physiological stresses are anticipated. Further, preconditioning is a valuable tool to study the possible mechanisms involved in cell death. Similar to the concept that coagulation and inflammation involve a finely tuned balance between proand anti-factors, pathways leading to cell death also demonstrate this balance. The study of cell death has typically emphasized pro-factors, likely because cell death is a relatively easily-measured endpoint. Preconditioning however, is widely understood to involve the induction of cyto-protective factors and therefore is an important tool to elucidate anti-factors or innate cyto-protective mechanisms. Examples of preconditioning are plentiful. For example, the induction of robust cyto-protective mechanisms is involved in many of the wondrous feats of nature such as prolonged submersion of diving mammals and hibernation. In clinical medicine, examples of preconditioning include the potential protective effects of pre-existing angina to the survival of patients with myocardial infarction3 or the value of short interruptions of coronary flow during percutaneous transluminal coronary angioplasty prior to the prolonged balloon inflation.4 Indeed there is now a body of literature that has established the human application of myocardial ischemic preconditioning.5 Aside from ancient remedies or possibly even homeopathy, the early demonstration of preconditioning was initially described in 1964 when it was noted that global hypoxia protected brain metabolism during subsequent hypoxia.6 Since then, the study of preconditioning has been pursued in efforts to create and understand the induction of ischemic and hypoxic tolerance. Typically, a preconditioning experiment comprises ischemia or hypoxia involving the organ of interest followed by the evaluation of the effects of subsequent exposure to ischemia or hypoxia. Interrupting certain pathways and demonstrating attenuation of tolerance would then constitute evidence that the pathway is involved in endogenous cyto-protection. Many potential injurious pathways have been implicated in ischemic injury in the brain. Correspondingly, there are many related sources of stress other than ischemia/hypoxia that can in turn induce ischemic/hypoxic tolerance. For example, there are reports of hypothermia and hyperthermia,7,8 inflammation,9 epilepsy,10 oxygen free radicals11,12 and hyperbaric oxygen13,14 inducing ischemic or hypoxic tolerance. Because of the interwoven nature of many of the cascades involved in ischemic or hypoxic brain injury, induction of tolerance to one ischemia-related stress may be initiated through another trigger. Further, even remote preconditioning has been described, where coronary endothelial ischemic tolerance was increased following transient limb ischemia,15 presumably through an effect that modified neutrophil activation.16 In this issue of the Journal, Zhang et al.17 present a preconditioning experiment with several messages. At first take, it seems unusual to be inducing ischemic preconditioning with an enriched oxygen supply rather than a restricted one. Nevertheless, it has already been reported by this group and others that hyperoxia and hyperbaric oxygen are indeed triggers for ischemic preEDITORIAL 201