Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations

Simon R. Clark, Catherine J. McMahon, Iva Gueorguieva, Malcolm Rowland, Sylvia Scarth, Rachel Georgiou, Pippa J. Tyrrell, Stephen J. Hopkins, Nancy J. Rothwell

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The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12±2 μg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22±4 μg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit. © 2008 ISCBFM All rights reserved.
Original languageEnglish
Pages (from-to)387-394
Number of pages7
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number2
Publication statusPublished - Feb 2008


  • IL-1RA
  • Inflammation
  • Ischaemia
  • Pharmacokinetics
  • Stroke
  • Sub-arachnoid haemorrhage


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