Summary

• An increased resistance to ischaemic injury, known as 'ischaemic tolerance', can be realized in the brain if the tissue is exposed previously to a non-damaging stressor, in a process known as 'preconditioning'. Therefore, endogenous pro-survival mechanisms are present in the CNS that can be coaxed from dormancy by the appropriate stimulus.
• Mechanistically, these 'programmed cell survival' responses may parallel the greater resistance of the neonate brain to oxygen deprivation, of genetically- and physiologically-acclimatized, high altitude natives, and of breath-holding and hibernating animals that withstand prolonged periods of hypoxia/anoxia.
• Effective preconditioning stimuli are numerous and diverse, suggesting that a downstream convergence of signalling pathways promotes this protective response.
• Two periods of tolerance can be induced by preconditioning: one appears rapidly (within minutes) as a result of post-translational responses, and the other, classical form of tolerance is delayed (by many hours, or even days), secondary to a dependency on altered gene expression. Both responses are transient, but can be induced repeatedly.
• Unique sensors (such as receptors), signal transduction pathways and transcription factors transduce the preconditioning stimulus into a multitude of gene expression changes that are ultimately responsible for the ischaemia-tolerant phenotype.
• Adaptive changes on the part of all resident brain cells, including different glial and vascular cells, contribute to the overall protection induced by preconditioning.
• Elucidating the molecular basis of these innate protective mechanisms might provide new therapeutic targets for ischaemic stroke, and perhaps for other neurodegenerative diseases.