Systemic inflammation impairs tissue reperfusion through endothelin-dependent mechanisms in cerebral ischemia

Katie N. Murray, Sylvie Girard, William M. Holmes, Laura M. Parkes, Stephen R. Williams, Adrian R. Parry-Jones, Stuart M. Allan

Research output: Contribution to journalArticlepeer-review


Background and Purpose-Systemic inflammation contributes to diverse acute and chronic brain pathologies, and extensive evidence implicates inflammation in stroke susceptibility and poor outcome. Here we investigate whether systemic inflammation alters cerebral blood flow during reperfusion after experimental cerebral ischemia. Methods-Serial diffusion and perfusion-weighted MRI was performed after reperfusion in Wistar rats given systemic (intraperitoneal) interleukin-1β or vehicle before 60-minute transient middle cerebral artery occlusion. The expression and location of endothelin-1 was assessed by polymerase chain reaction, ELISA, and immunofluorescence. Results-Systemic interleukin-1 caused a severe reduction in cerebral blood flow and increase in infarct volume compared with vehicle. Restriction in cerebral blood flow was observed alongside activation of the cerebral vasculature and upregulation of the vasoconstricting peptide endothelin-1 in the ischemic penumbra. A microthrombotic profile was also observed in the vasculature of rats receiving interleukin-1. Blockade of endothelin-1 receptors reversed this hypoperfusion, reduced tissue damage, and improved functional outcome. Conclusions-These data suggest patients with a raised inflammatory profile may have persistent deficits in perfusion after reopening of an occluded vessel. Future therapeutic strategies to interrupt the mechanism identified could lead to enhanced recovery of penumbra in patients with a heightened inflammatory burden and a better outcome after stroke.

Original languageEnglish (US)
Pages (from-to)3412-3419
Number of pages8
Issue number11
StatePublished - 2014


  • Brain ischemia
  • Endothelin-1
  • Inflammation
  • Interleukin-1
  • Magnetic resonance imaging
  • Reperfusion

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing


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