Abstract
Stroke is one of the leading causes of morbidity and mortality worldwide, and it is increasing in prevalence. The limited therapeutic window and potential severe side effects prevent the widespread clinical application of the venous injection of thrombolytic tissue plasminogen activator and thrombectomy, which are regarded as the only approved treatments for acute ischemic stroke. Triggered by various types of mild stressors or stimuli, ischemic preconditioning (IPreC) induces adaptive endogenous tolerance to ischemia/reperfusion (I/R) injury by activating a multitude cascade of biomolecules, for example, proteins, enzymes, receptors, transcription factors, and others, which eventually lead to transcriptional regulation and epigenetic and genomic reprogramming. During the past 30 years, IPreC has been widely studied to confirm its neuroprotection against subsequent I/R injury, mainly including local ischemic preconditioning (LIPreC), remote ischemic preconditioning (RIPreC), and cross preconditioning. Although LIPreC has a strong neuroprotective effect, the clinical application of IPreC for subsequent cerebral ischemia is difficult. There are two main reasons for the above result: Cerebral ischemia is unpredictable, and LIPreC is also capable of inducing unexpected injury with only minor differences to durations or intensity. RIPreC and pharmacological preconditioning, an easy-to-use and non-invasive therapy, can be performed in a variety of clinical settings and appear to be more suitable for the clinical management of ischemic stroke. Hoping to advance our understanding of IPreC, this review mainly focuses on recent advances in IPreC in stroke management, its challenges, and the potential study directions.
Highlights
Cerebrovascular disease is one of the main diseases that lead to human death and disability worldwide, which endangers the health and life of middle-aged and elderly people [1, 2]
There are mainly four different experimental ischemic duration modes: [1] global ischemic preconditioning through two- or four-vessel occlusion before final global ischemia [22, 44,45,46], [2] global ischemic preconditioning by four-vessel occlusion before permanent focal ischemia [47], [3] focal ischemic preconditioning by transient middle cerebral artery occlusion (MCAO) followed by permanent MCAO in rats [109], [4] focal ischemic preconditioning induced by unilateral MCAO followed by global ischemia [25, 110]
ischemic preconditioning (IPreC) strategies involve the application of non-lethal but noxious stressors or stimuli, but an inevitable problem is that preconditioning stimuli have the potential to cause fatal damage
Summary
Cerebrovascular disease is one of the main diseases that lead to human death and disability worldwide, which endangers the health and life of middle-aged and elderly people [1, 2]. LIPreC, one of the earliest mechanical methods for mediating IPreC, can induce cerebral protective tolerance to the subsequent prolonged lethal I/R injury by short-term I/R of the brain tissue [92]. Some previous clinical research concerning stroke patients has shown that TIAs can mediate the protective ischemic tolerance of brain tissue to subsequent lethal cerebral ischemia to a certain extent. DNA microarray technology, an efficient method for studying differential gene expression patterns of ischemic tolerance, were used to imply the genetic profile in IPreC-stimulated rat hippocampal slices and mouse cortex [118, 214], by which the genes related to cell survival and regeneration (such as HIF, insulin-like growth factor, etc.) are upregulated, and region-specific expression patterns can be observed apparently [215]. Other ischemic tolerance-inducing stimuli include exercise and transcranial low-level light therapy [254, 255]
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