Abstract and Introduction
Purpose of review: Ischemic preconditioning (IPC) is gaining attention as a novel neuroprotective therapy and could provide an improved mechanistic understanding of tolerance to cerebral ischemia. The purpose of this article is to review the recent work in the field of IPC and its applications to clinical scenarios.
Recent findings: The cellular signaling pathways that are activated following IPC are now better understood and have enabled investigators to identify several IPC mimetics. Most of these studies were performed in rodents, and efficacy of these mimetics remains to be evaluated in human patients. Additionally, remote ischemic preconditioning (RIPC) may have higher translational value than IPC. Repeated cycles of temporary ischemia in a remote organ can activate protective pathways in the target organ, including the heart and brain. Clinical trials are underway to test the efficacy of RIPC in protecting brain against subarachnoid hemorrhage.
Summary: IPC, RIPC, and IPC mimetics have the potential to be therapeutic in various clinical scenarios. Further understanding of IPC-induced neuroprotection pathways and utilization of clinically relevant animal models are necessary to increase the translational potential of IPC in the near future.
Cerebral ischemia resulting from cardiac arrest and stroke is one of the leading causes of mortality and morbidity in the world. During decades of research, a large number of neuroprotective agents have shown efficacy in animal models but have failed in clinical trials. This failure may have been because of the use of wrong animal models, poor design of clinical trials, and the use of dosages that are much lower than those utilized in animal studies, among many others. As a result, investigators have been pushed to rethink the strategies to develop new therapies for cerebral ischemia. One new strategy that has recently gained attention is ischemic preconditioning (IPC).
The phenomenon of IPC was discovered when studies in rabbit heart demonstrated that induction of mild ischemia followed by a period of reperfusion made the heart more resistant to a subsequent, ordinarily lethal ischemic insult. IPC has since proven to be a powerful strategy to induce tolerance to ischemic insults in most organs studied and has been replicated in many laboratories around the world.
IPC in brain consists of an early and a late phase, during which different neuroprotective responses are elicited in specific time windows (time interval between the first sublethal insult and the second, ordinarily lethal insult). There is a rapid phase for which the cumulative protective effect of released factors is maximal if the window between initial and final insult is approximately 1 h in duration.[3–5] The combination of released factors and activated pathways in the second phase, defined as delayed preconditioning,[6,7] elicits maximum protection if the window is extended to several days after the preconditioning insult, and has been shown to provide more robust and longer lasting neuroprotection than the first phase. It is now understood that IPC comprises several key steps,[8,9] during which triggering factors are released in response to the short-duration sublethal ischemic insult; signaling pathways are activated by the receptors of the triggering factors; and gene expression is orchestrated by the delayed preconditioning-activated signaling pathways. Activation of these pathways results in brain cells having a phenotype that is highly resistant to ischemic insults.
Although many triggering factors are activated by IPC, our laboratory has shown two such factors to be critical, and they appear to have opposite effects. We and others showed that adenosine is released after IPC and initiates a signaling pathway that promotes ischemic tolerance in brain via activation of A1 receptors (A1AR).[4,10,11] Adenosine is a neuromodulator and vasomodulator that is normally released when ATP levels decline. Inhibition of synaptic activity is observed when adenosine binds to the A1 receptor, which is believed to be the key receptor in the induction of ischemic tolerance.
In contrast to the inhibitory pathway activated by adenosine, we and others have shown that activation of excitatory postsynaptic NMDA receptors is also required for IPC-induced ischemic tolerance in brain.[13–16] It is now known that these two receptors (NMDA receptors and A1AR), via different mechanisms, activate a novel type of protein kinase C (εPKC)[13,17] which plays a key role in the induction of ischemic tolerance. Although there are multiple key signaling pathways that mediate preconditioning, it is plausible that significant cross-talk occurs among pro-survival kinases following IPC. As this area of research is beyond the scope of this review, the reader is directed to previously written reviews that provide an overview of these signaling pathways and their effect on IPC.[8,9,18,19,20]
Cerebral ischemia targets many sensitive cellular sites that seldom recover thereafter. Owing to the excitotoxicity that ensues following cerebral ischemia, synaptic plasticity and functional recovery are significantly impaired. In addition, mitochondria are particularly sensitive to both the ischemic insult as well as the reperfusion phase. IPC, via activation of key survival signaling pathways, promotes synaptic and mitochondrial alterations that make neurons more resistant to ischemia. In the following sections, we will describe some of these effects mediated by IPC.
Curr Opin Neurol. 2013;26(1):1-7. © 2013 Lippincott Williams & Wilkins