Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats

Jesus M Pradillo, Adam Denes, Andrew D Greenhalgh, Herve Boutin, Caroline Drake, Barry W McColl, Eleanor Barton, Spencer D Proctor, James C Russell, Nancy J Rothwell, Stuart M Allan

Research output: Contribution to journalArticlepeer-review

Abstract

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.
Original languageEnglish
Pages (from-to)1810-9
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume32
Issue number9
DOIs
Publication statusPublished - Sep 2012

Keywords

  • Animals
  • Blood-Brain Barrier
  • Brain
  • Brain Ischemia
  • Cytokines
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery
  • Inflammation
  • Interleukin 1 Receptor Antagonist Protein
  • Ischemic Attack, Transient
  • Lymphocyte Activation
  • Magnetic Resonance Imaging
  • Male
  • Microglia
  • Neuroprotective Agents
  • Neutrophil Infiltration
  • Rats
  • Recombinant Proteins
  • Reperfusion
  • Stroke
  • Treatment Outcome

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