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

Abstract

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 microg/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 microg/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.

• Authors: Simon R Clark, Catherine J McMahon, Iva Gueorguieva, Malcolm Rowland, Sylvia Scarth, Rachel Georgiou, Pippa J Tyrrell, Stephen J Hopkins, Nancy J Rothwell
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 28 Issue 2 Pg. 387-94 (Feb 2008) ISSN: 0271-678X [Print] United States
• PMID: 17684519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin 1 Receptor Antagonist Protein
• Neuroprotective Agents

Topics

• Adult
• Aged
• Animals
• Brain (metabolism)
• Brain Ischemia (drug therapy, metabolism)
• Female
• Humans
• Infarction, Middle Cerebral Artery (drug therapy, pathology)
• Infusions, Intravenous
• Interleukin 1 Receptor Antagonist Protein (blood, cerebrospinal fluid, pharmacokinetics)
• Male
• Middle Aged
• Middle Cerebral Artery (physiology)
• Neuroprotective Agents (blood, cerebrospinal fluid, pharmacokinetics)
• Rats
• Rats, Sprague-Dawley
• Subarachnoid Hemorrhage (metabolism)