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Modulation of the peri-infarct neurogliovascular function by delayed COX-1 inhibition
Evelyn M R Lake1,2, James Mester2, Lynsie Am Thomason3
1Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut, USA.
Purpose:
Stroke is the leading cause of adult disability worldwide. The absence of more effective interventions in the chronic stage-that most patients stand to benefit from-reflects 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 Methods:
FR122047 (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.
Results:
Stroke caused an increase in perilesional resting perfusion (peri-/contralesional perfusion ratio of 170 ± 10%) and perfusion responses to hypercapnia (180 ± 10%) at 7 days. At 21 days, placebo-administered rats showed normalized perilesional perfusion (100 ± 20%) but persistent hyperreactivity (190 ± 20%). 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; R2 = 0.7, P = 0.03).
Conclusion:
These 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.
Insights
Selective cyclooxygenase-1 (COX-1) inhibition after stroke improved blood flow and neuronal survival. This novel treatment offers potential benefits for chronic stroke recovery by targeting the neurogliovascular unit.
Area of Science:
- Neuroscience
- Ischemic Stroke Research
- Pharmacology
Background:
- Stroke is a primary cause of adult disability globally.
- Effective chronic-stage interventions are limited due to incomplete understanding of recovery mechanisms.
Purpose of the Study:
- To investigate the effects of selective cyclooxygenase-1 (COX-1) inhibition on chronic focal ischemia.
- To explore the role of COX-1 in post-stroke recovery and neurogliovascular unit function.
Main Methods:
- Adult male rats with focal cortical ischemia were treated with a COX-1 inhibitor (FR122047) starting 7 days post-stroke.
- Longitudinal arterial spin labeling MRI assessed resting perfusion and hypercapnia reactivity at 7 and 21 days post-stroke.
- Immunohistochemistry evaluated neuronal survival, endothelial density, and neuroinflammation (microglia, astrocytes).
Main Results:
- Stroke induced perilesional hyperperfusion and hyperreactivity, which persisted in placebo-treated rats.
- COX-1 inhibition sustained perilesional hyperperfusion and normalized perfusion reactivity.
- Treated rats showed increased neuronal survival and reduced microglia/macrophage recruitment compared to controls.
- Perilesional perfusion positively correlated with neuronal survival.
Conclusions:
- Delayed selective COX-1 inhibition demonstrates multifaceted benefits for the neurogliovascular unit post-stroke.
- These findings highlight COX-1's role in chronic ischemic injury and recovery.
- Targeting COX-1 may represent a novel therapeutic strategy for improving chronic stroke outcomes.
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