Intracisternal Interleukin-1 Receptor Antagonist Prevents Postoperative Cognitive Decline and Neuroinflammatory Response in Aged Rats

Abstract

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.