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

J Magn Reson Imaging. 2017 Aug;46(2):505-517. doi: 10.1002/jmri.25541. Epub 2016 Nov 7.

Abstract

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.

Keywords: COX-1; focal ischemia; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclooxygenase 1
  • Cyclooxygenase Inhibitors / pharmacology*
  • Disease Models, Animal
  • Endothelin-1 / chemistry
  • Ischemia / diagnostic imaging*
  • Macrophages / pathology
  • Magnetic Resonance Imaging*
  • Male
  • Membrane Proteins / antagonists & inhibitors*
  • Microglia / pathology
  • Neuroglia / pathology
  • Neurons / pathology
  • Perfusion
  • Piperazines / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Spin Labels
  • Stroke / diagnostic imaging*
  • Stroke / physiopathology*
  • Thiazoles / chemistry

Substances

  • Cyclooxygenase Inhibitors
  • Endothelin-1
  • Membrane Proteins
  • Piperazines
  • Spin Labels
  • Thiazoles
  • 1-((4,5-bis(4-methoxyphenyl)-2-thiazoyl)carbonyl)-4-methylpiperazine
  • Cyclooxygenase 1
  • Ptgs1 protein, rat

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