Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats.
To investigate the role of the pro-inflammatory cytokine interleukin-1β (IL-1β) in postoperative cognitive dysfunction (POCD) in aged rats, we used laparotomy to mimic human abdominal surgery in adult (3 months) and aged (24 months) F344/BN rats. We demonstrated that memory consolidation of the hippocampal-dependent contextual fear-conditioning task is significantly impaired in aged but not young rats 4 d after surgery. Hippocampal-independent auditory-cued fear memory was not disrupted by laparotomy in either age group. The hippocampal-dependent memory impairment was paralleled by elevations of IL-1β in the hippocampus of aged animals 1 and 4 d after surgery. These findings support our substantial line of previous research showing that aged animals are more vulnerable to cognitive decline after a peripheral immune challenge. In addition, we demonstrated that a single intracisternal administration of interleukin-1 receptor antagonist (IL-1RA; 112 μg) at the time of surgery was sufficient to block both the behavioral deficit and the neuroinflammatory response. Injecting the same dose of IL-1RA peripherally failed to have a protective effect. These data provide strong support for the specific role of central, not peripheral, IL-1β in POCD. Furthermore, the long-lasting presence of IL-1RA in the brain (4 d) compared with in the blood (<24 h) underscores the value of intracisternal administration of IL-1RA for therapeutic purposes.
Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, USA. ruth.barrientos@colorado.edu
Ruth M
RM
Barrientos
Amy M
AM
Hein
Matthew G
MG
Frank
Linda R
LR
Watkins
Steven F
SF
Maier
D000375:Aging / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D002946:Cisterna Magna / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D007276:Injections, Intraventricular; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D011183:Postoperative Complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1