Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations
| Autor: | Catherine McMahon, Nancy J. Rothwell, Malcolm Rowland, Rachel Georgiou, Stephen J. Hopkins, Simon R Clark, Sylvia Scarth, Pippa J. Tyrrell, Iva Gueorguieva |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Middle Cerebral Artery medicine.drug_class Ischemia Pharmacology Neuroprotection Brain Ischemia Proinflammatory cytokine Rats Sprague-Dawley Cerebrospinal fluid medicine Animals Humans Infusions Intravenous Aged business.industry Brain Interleukin Infarction Middle Cerebral Artery Human brain Middle Aged Subarachnoid Hemorrhage medicine.disease Receptor antagonist Rats Interleukin 1 Receptor Antagonist Protein Neuroprotective Agents Interleukin 1 receptor antagonist medicine.anatomical_structure Neurology Anesthesia Female Neurology (clinical) Cardiology and Cardiovascular Medicine business |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism. 28:387-394 |
| ISSN: | 1559-7016 0271-678X |
| DOI: | 10.1038/sj.jcbfm.9600537 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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