Ischaemic preconditioning of the brain, mechanisms and applications

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Abstract
Background. The concept of ischaemic preconditioning was introduced in the late 1980s. The concept emerged that a brief subcritical ischaemic challenge could mobilize intrinsic protective mechanisms that increased tolerance against subsequent critical ischaemia. Tissues with a high sensitivity against ischaemia, i.e. myocardium and central nervous system, present the most promising targets for therapeutic application of ischaemic preconditioning. During the last years the mechanisms of neuronal preconditioning were systematically studied and a number of molecular regulation pathways were discovered to participate in preconditioning. The purpose of the present review is to survey the actual knowledge on cerebral preconditioning, and to define the practical impact for neurosurgery. Methods. A systematic medline search for the terms preconditioning and postconditioning was filed. Publications related to the nervous system were selected and analysed. Findings. Preconditioning can be subdivided into early and late mechanisms, depending on whether the effect appears immediately after the nonlethal stress or with a delay of some hours or days. In general early effects can be linked to adaptation of membrane receptors whereas late effects are the result of gene up- or downregulation. Not only subcritical ischaemia can trigger preconditioning but also hypoxia, hyperthermia, isoflurane and other chemical substances. Although a vast amount of knowledge has been accumulated regarding neural preconditioning, it is unknown whether the effects can be potentiated by pharmacological or hypothermic neuroprotection during the critical ischaemia. Furthermore, although the practical importance of these findings is obvious, the resulting protective manipulations have so far not been transferred into clinical neurosurgery. Postconditioning and remote ischaemic preconditioning are additional emerging concepts. Postconditioning with a series of mechanical interruptions of reperfusion can apparently reduce ischaemic damage. Remote ischaemic preconditioning refers to the concept that transient ischaemia for example of a limb can lead to protection of the myocardium and possibly the brain. Conclusion. Possible cumulative neuroprotection by preconditioning and pharmacological protection during critical ischaemia should be studied systematically. Easy to apply methods of preconditioning, such as the application of volatile anaesthetics or erythropoietin some hours or days prior to planned temporary ischaemia, should be introduced into the practice of operative neurosurgery.