Delayed post-ischemic conditioning significantly improves the outcome after retinal ischemia

Abstract

In previous studies, it was shown that post-conditioning, a transient period of brief ischemia following prolonged severe ischemia in the retina, could provide significant improvement in post-ischemic recovery, attenuation of cell loss, and decreased apoptosis. These studies showed that post-conditioning effectively prevented damage after retinal ischemia when it was instituted early (within one hour) in the post-ischemic period. While post-ischemic conditioning holds high promise of clinical translation, patients often present late after the onset of retinal ischemia and therefore immediate application of this anti-ischemic maneuver is generally not feasible. In this study, we examined the hypothesis that application of a post-conditioning stimulus at 24 h or greater following the end of prolonged ischemia would decrease the extent of ischemic injury. Ischemia was induced in rat retina in vivo. Recovery after ischemia followed by 5 minutes of post-conditioning brief ischemia 24 or 48 h after prolonged ischemia was assessed functionally (electroretinography) and histologically at 7 days after ischemia and post-conditioning or sham post-conditioning. We found that the brief ischemic stimulus applied 24, but not 48 h after prolonged ischemia significantly improved functional recovery and decreased histological damage induced by prolonged ischemia. We conclude that within a defined time window, delayed post-ischemic conditioning ameliorated post-ischemic injury in rats. Compared to earlier studies, the present work demonstrates for the first time the novel ability of a significantly delayed ischemic stimulus to provide robust neuroprotection in the retina following ischemia.

Pharmacologic inhibition of reactive gliosis blocks TNF-α-mediated neuronal apoptosis

“…For example, ischemic preconditioning has been reported to have protective effects that are partially attributed to activated glia. 80 , 81 , 82 The mechanism underlying this protection remains unclear, and is likely influenced by signaling through additional metabolic response pathways that may differ from the p38 driven mechanism we have described here. A key goal for the present work is the targeted inhibition of IFs, rather than complete ablation of the reactive cascade.…”

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

“…The ERG a-, b-, OPs and P2-waves from ischemic eyes 7 days after ischemia in the groups for comparison were expressed as normalized intensity-response plots with stimulus intensity (log cd·s·m −2 ) on the x-axis, and corresponding percent recovery of the baseline on the y-axis, as we previously reported in multiple publications (for example and details, see [25]). Specifically, to account for variation in the electroretinogram amplitudes (that is, including the known day-to-day variation within animals), values obtained for follow-up examinations after ischemia ended were corrected by dividing the normalized ischemic value by the normalized control value (control electroretinogram amplitude at a given time point divided by the baseline control), as we have earlier reported.…”

“…This analysis corrects for day-to-day expected variation in amplitudes of the ERG waveforms, and for any effects of injection into the control eye. [25] To minimize variability, recordings were made in animals at approximately the same time of day. Recorded amplitude, time course, and intensity were exported and analyzed in Matlab 2011a (The MathWorks, Natick, MA) as previously described [16].…”

Stroke research at a crossroad: asking the brain for directions

“…Remote PC has been tested in a phase I trial of subarachnoid hemorrhage to protect the brain form delayed ischemic lesions, a major cause of morbidity and mortality in this stroke type, and was found to be safe and well tolerated 44 . Importantly, remote PC is also effective in reducing brain and retinal ischemic injury after it has occurred (post-conditioning) 45,46 , and is being tested in clinical trials (ClinicalTrial.gov identifier: NCT00975962). Remote post-conditioning is attractive because of its safety, simplicity and low cost, but its feasibility, effectiveness and potential downsides in ischemic stroke need to be established.…”