Interleukin-1 receptor antagonist attenuates regional neuronal cell death and cognitive dysfunction after experimental brain injury.
The effect of systemic administration of human recombinant interleukin-1 receptor antagonist (rhIL-1ra) on behavioral outcome and histopathologic damage after lateral fluid-percussion brain injury of moderate severity was evaluated. In study 1, brain-injured Sprague Dawley rats received timed subcutaneous injections beginning 15 minutes after injury of either 100 mg/kg rhIL-1ra (high dose, total dose = 1900 mg/kg), 10 mg/kg rhIL-1ra (low dose, total dose = 190 mg/kg), or vehicle over 7 days. No effect of low-dose rhIL-1ra was observed in study 1. High-dose rhIL-1ra significantly attenuated posttraumatic neuronal loss in the injured hippocampal CA3 region (P < 0.05), dentate hilus (P < 0.05), and cortex (P < 0.05) but impaired recovery of motor function at 7 days after trauma (P < 0.05). In study 2, rats were pretrained to learn a visuospatial task in a Morris water maze, subjected to fluid-percussion brain injury or sham treatment, and randomly assigned to receive multiple subcutaneous injections at timed intervals of 100 mg/kg rhIL-1ra (total dose = 900 mg/kg) or vehicle over 42 hours, followed by continuous infusion of a lower concentration of rhIL-1ra (20 mg/kg/day, total dose = 100 mg/kg), or vehicle for 5 days using subcutaneously implanted osmotic minipumps. Postinjury administration of rhIL-1ra significantly attenuated cognitive deficits compared with vehicle-treated animals at 42 hours (P < 0.05) but did not affect motor function at 48 hours, 1 week, and 2 weeks. These results suggest that inhibitors of cytokine pathways may be therapeutically useful for the treatment of brain trauma.
Sanderson
K L
KL
Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA.
Raghupathi
R
R
Saatman
K E
KE
Martin
D
D
Miller
G
G
McIntosh
T K
TK
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001522:Behavior, Animal; D001923:Brain Chemistry / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D018782:Maze Learning; D009043:Motor Activity; D009474:Neurons / Q000166:cytology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D011524:Protoporphyrins; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; C017803:zinc protoporphyrin