Delayed Postconditioning Protects against Focal Ischemic Brain Injury in Rats

Abstract

BackgroundWe and others have reported that rapid ischemic postconditioning, interrupting early reperfusion after stroke, reduces infarction in rats. However, its extremely short therapeutic time windows, from a few seconds to minutes after reperfusion, may hinder its clinical translation. Thus, in this study we explored if delayed postconditioning, which is conducted a few hours after reperfusion, offers protection against stroke.Methods and ResultsFocal ischemia was generated by 30 min occlusion of bilateral common carotid artery (CCA) combined with permanent occlusion of middle cerebral artery (MCA); delayed postconditioning was performed by repetitive, brief occlusion and release of the bilateral CCAs, or of the ipsilateral CCA alone. As a result, delayed postconditioning performed at 3h and 6h after stroke robustly reduced infarct size, with the strongest protection achieved by delayed postconditioning with 6 cycles of 15 min occlusion/15 min release of the ipsilateral CCA executed from 6h. We found that this delayed postconditioning provided long-term protection for up to two months by reducing infarction and improving outcomes of the behavioral tests; it also attenuated reduction in 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-uptake therefore improving metabolism, and reduced edema and blood brain barrier leakage. Reperfusion in ischemic stroke patients is usually achieved by tissue plasminogen activator (tPA) application, however, t-PA's side effect may worsen ischemic injury. Thus, we tested whether delayed postconditioning counteracts the exacerbating effect of t-PA. The results showed that delayed postconditioning mitigated the worsening effect of t-PA on infarction.ConclusionDelayed postconditioning reduced ischemic injury after focal ischemia, which opens a new research avenue for stroke therapy and its underlying protective mechanisms.

Postconditioning: a new or old option after ischemic stroke?

“…It appears to provide long-term protection and improved neuro logical function, and partially reversed the detrimental effect of t-PA [5]. Such a novel neuroprotective model offers an alternative and promising avenue for studying therapeutic strategies against stroke.…”

“…The protective effect of postconditioning can be achieved by occluding the ipsilateral common carotid artery (CCA), which is clinically relevant, for the ipsilateral CCA is accessible [5]. In addition, postconditioning can also be induced via volatile anesthetics [13,14].…”

“…The multiplicity of cell types that are affected by postconditioning (i.e., vascular endothelial cells and inflammatory cells) reflects the complexity of reperfusion injury and suggests a wide network of effects within this complex interactive web of responses. In addition, delayed postconditioning, which is clinically more relevant, also improved glucose uptake, inhibited edema and mitigated blood-brain barrier leakage in the penumbra, and lastly, attenuated the exacerbating effect of tissue plasminogen activator (t-PA) [5].…”

“…The neuroprotective effects of postconditioning depend mainly on the degree of ischemia [12], the onset time of postconditioning [16,17], and the cycle number of occluding and releasing the blood vessels [5,16].…”

“…These injury cascades are interconnected in complex ways, thus it is hard to compare their pathogenic importance in ischemia models [5]. The research in cellular and molecular pathways has spurred the studies in potential neuroprotections mainly in pharmacological fields, such as anti-excitotoxic treatment, calcium-channel antagonism, approaches for inhibition of oxidation, inflammation and apoptosis [6,7].…”