Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood–brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia ( Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: “symptomatic salvaged tissue” (SST) and “asymptomatic infarcted tissue” (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia–reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

In acute ischemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic hemorrhagic transformation. However, the available techniques assessing blood–brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood–brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood–brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (< 1 nm), and AGuIX® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced MRI, the baseline transfer constant Ktrans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] x10−3 min−1, respectively, in normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] x10−3 min−1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, Ktrans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] x10−3 min−1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, Ktrans also increased within the ischemic growth areas, suggesting added value for AGuIX®. Finally, Ktrans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo (n = 5). Ktrans quantification with AGuIX® nanoparticles can monitor early blood–brain barrier damage and treatment effect in ischemic stroke after reperfusion.