Modulation of the peri-infarct neurogliovascular function by delayed COX-1 inhibition.

PurposeStroke is the leading cause of adult disability worldwide. The absence of more effective interventions in the chronic stagethat most patients stand to benefit fromreflects uncertainty surrounding mechanisms that govern recovery. The present work investigated the effects of a novel treatment (selective cyclooxygenase-1, COX-1, inhibition) in a model of focal ischemia. Materials and MethodsFR122047 (COX-1 inhibitor) was given beginning 7 days following stroke (cortical microinjection of endothelin-1) in 23 adult male rats. Longitudinal continuous-arterial-spin-labeling was performed prior to treatment (7 days), and repeated following treatment (21 days) on a 7T magnetic resonance imaging (MRI) system to estimate resting perfusion and reactivity to hypercapnia. These in vivo measurements were buttressed by immunohistochemistry. ResultsStroke caused an increase in perilesional resting perfusion (peri-/contralesional perfusion ratio of 17010%) and perfusion responses to hypercapnia (18010%) at 7 days. At 21 days, placebo-administered rats showed normalized perilesional perfusion (10020%) but persistent hyperreactivity (19020%). Treated animals exhibited sustained perilesional hyperperfusion (180 +/- 10%). Further, reactivity lateralization did not persist following treatment (peri- vs. contralesional reactivity: P=0.002 at 7 vs. P=0.2 at 21 days). Hemodynamic changes were accompanied by neuronal loss, increased endothelial density, and widespread microglial and astrocytic activation. Moreover, relative to controls, treated rats showed increased perilesional neuronal survival (22 +/- 1% vs. 14.9 +/- 0.8%, P=0.02) and decreased microglia/macrophage recruitment (17 +/- 1% vs. 20 +/- 1%, P=0.05). Finally, perilesional perfusion was correlated with neuronal survival (slope=0.14 +/- 0.05; R-2=0.7, P=0.03). ConclusionThese findings shed light on the role of COX-1 in chronic ischemic injury and suggest that delayed selective COX-1 inhibition exerts multiple beneficial effects on the neurogliovascular unit. Level of Evidence: 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:505-517