Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection

Br J Pharmacol. 2010 May;160(1):153-9. doi: 10.1111/j.1476-5381.2010.00684.x.


Background and purpose: Limited data on the brain penetration of potential stroke treatments have been cited as a major weakness contributing to numerous failed clinical trials. Thus, we tested whether interleukin-1 receptor antagonist (IL-1RA), established as a potent inhibitor of brain injury in animals and currently in clinical development, reaches the brain via a clinically relevant administration route, in experimental stroke.

Experimental approach: Male, Sprague-Dawley rats [either naïve or exposed to middle cerebral artery occlusion (MCAo)] were given a single s.c. dose of IL-1RA (100 mg*kg(-1)). The pharmacokinetic profile of IL-1RA was assessed in plasma and CSF up to 24 h post-administration. Brain tissue distribution of administered IL-1RA was assessed using immunohistochemistry. In a separate experiment, the neuroprotective effect of the single s.c. dose of IL-1RA in MCAo was assessed versus a placebo control group.

Key results: A single s.c. dose of IL-1RA reduced damage caused by MCAo by 33%. This dose resulted in sustained, high concentrations in plasma and CSF, penetrated brain tissue exclusively in areas of blood-brain barrier breakdown and co-localized with morphologically viable neurones. CSF concentrations did not reflect massive parenchymal infiltration of IL-1RA in MCAo animals compared to naïve.

Conclusions and implications: These data are the first to show that a potential treatment for stroke, IL-1RA, rapidly reaches salvageable brain tissue via an administration route that is clinically relevant. This allows confidence that IL-1RA, as a candidate for further clinical development, is able to confer its protective actions both peripherally and centrally.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism*
  • Brain / pathology
  • Brain Infarction / drug therapy
  • Brain Infarction / metabolism
  • Brain Infarction / pathology
  • Interleukin 1 Receptor Antagonist Protein / administration & dosage
  • Interleukin 1 Receptor Antagonist Protein / pharmacokinetics*
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Ischemic Attack, Transient / drug therapy
  • Ischemic Attack, Transient / metabolism*
  • Ischemic Attack, Transient / pathology
  • Male
  • Neuroprotective Agents / pharmacokinetics*
  • Neuroprotective Agents / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Tissue Distribution


  • Interleukin 1 Receptor Antagonist Protein
  • Neuroprotective Agents
  • Receptors, Interleukin-1