Neuroprotection by remote ischemic conditioning in the setting of acute ischemic stroke: a preclinical two-centre study

Abstract

Reperfusion is the only existing strategy for patients with acute ischemic stroke, however it causes further brain damage itself. A feasible therapy targeting reperfusion injury is remote ischemic conditioning (RIC). This was a two-centre, randomized, blinded international study, using translational imaging endpoints, aimed to examine the neuroprotective effects of RIC in ischemic stroke model. 80 male rats underwent 90-min middle cerebral artery occlusion. RIC consisted of 4 × 5 min cycles of left hind limb ischemia. The primary endpoint was infarct size measured on T2-weighted MRI at 24 h, expressed as percentage of the area-at-risk. Secondary endpoints were: hemispheric space-modifying edema, infarct growth between per-occlusion and 24 h MRI, neurofunctional outcome measured by neuroscores. 47 rats were included in the analysis after applying pre-defined inclusion criteria. RIC significantly reduced infarct size (median, interquartile range: 19% [8%; 32%] vs control: 40% [17%; 59%], p = 0.028). This effect was still significant after adjustment for apparent diffusion coefficient lesion size in multivariate analysis. RIC also improved neuroscores (6 [3; 8] vs control: 9 [7; 11], p = 0.032). Other secondary endpoints were not statistically different between groups. We conclude that RIC in the setting of acute ischemic stroke in rats is safe, reduces infarct size and improves functional recovery.

Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

“…Despite strong pre-clinical evidence of the effectiveness of RIC in protecting the heart and the brain against ischaemia/reperfusion injury, it has failed to translate into a clinical treatment of myocardial infarction or stroke. Studies conducted in young and healthy experimental animals reported that RIC can markedly reduce cortical infarcts [10,72,84]. Yet, clinical data show no major beneficial effect of RIC on stroke outcomes [68], although with some suggestion of reduced recurrent strokes with intracerebral artery stenosis treatment, and decreased stroke severity with carotid stenosis [69].…”

“…The animals were randomized into four experimental groups: (1) rats with MCAO/sham-RIC; (2) rats subjected to RIC starting 10 min before the onset of reperfusion; RIC protocol involved 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods [10,29], applied using an inflatable 12-mm cuff (IVM, USA). The cuff was inflated to 200 mmHg to stop the blood flow through the limb, as reported previously [12]; (3) rats with MCAO treated with a competitive GLP-1R antagonist Exendin (9-39) (Ex9, 50 μg kg −1 , intravenously) 20 min before the onset of reperfusion; (4) rats subjected to the RIC protocol starting 10 min before the onset of reperfusion and treated with Ex9 10 min prior to the first episode of RIC.…”

Contribution of preclinical MRI to responsible animal research: living up to the 3R principle

“…Marlene Wiart et al shared data from another preclinical stroke trial in rats that evaluated the neuroprotective effects of remote ischemic conditioning [11]. The primary endpoint was edema-corrected lesion size measured by T2-weighted MRI at 24 h of reperfusion normalized by the area-at-risk of infarction determined from per-occlusion MRI for each individual.…”

Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke

“…Exclusion rates are rarely reported in stroke research, which actually represents one of the methodological flaw of preclinical studies. Basalay et al recently reported a 25% exclusion rate at 24h post-surgery due to the combination of mortality rate and hemorrhagic transformations in a bicentre international study using the same tMCAO model in rats (37). For long-term studies, the mortality rate is increased as seen in the current study, where the mortality post-surgery exceeded our a priori hypothesis: this is a further element to be taken into account when designing a therapeutic trial to reach the adequate statistical power.…”