Abstract
Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.
Highlights
The incidence, mortality, and prevalence of neurological disorders are increasing worldwide, primarily because of the growing elderly population [1]
Prior administration of remote ischemic preconditioning (RIPreC) to patients undergoing endovascular procedure can potentially reduce the high risk of ischemic or haemorrhagic stroke insult after surgical treatments for several clinical settings including intracranial aneurysms and carotid endarterectomy [26,27,28,29]; [2] remote ischemic per-conditioning (RIPerC), which is applied during the ischemic event; and [3] remote ischemic post-conditioning (RIPostC), which is applied after the ischemic event or during reperfusion
The cytoprotection received through the phosphorylation of key prosurvival kinases of reperfusion injury salvage kinase (RISK) (Akt, Erk1/2, GSK-3β) and survivor activating factor enhancement (SAFE) (STAT3) pathways is dependent on the inhibition of mitochondrial permeability transition pore (mPTP), suggesting a key protective role for this pathway in molecular signaling induced by remote ischemic conditioning (RIC) [97]
Summary
The incidence, mortality, and prevalence of neurological disorders are increasing worldwide, primarily because of the growing elderly population [1]. Remote Ischemic Conditioning (RIC) is a therapy that involves brief, intermittent episodes of sublethal ischemia and reperfusion that is applied to a peripheral tissue, organ or a vascular territory This peripheral signal is transmitted to the distal target organ (e.g., brain or heart) to relay protection against prolonged ischemia and subsequent IR injury [14, 15]. A preconditioning (PC) intervention was directly applied to the dog heart via four cycles (each for 5 min) of alternative occlusion/reflow of the left anterior descending (LAD) coronary artery prior to initiation of 40 min cardiac ischemia [16] Their results showed that PC was associated with a considerable reduction in myocardial infarction size. In 1993 the conditioning concept was extended to remote ischemic conditioning (RIC), in which ischemia is induced to an organ far from the target organ, often using a blood pressure cuff, offering a safe and feasible approach [24]
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