Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats

J Neurosci. 2012 Oct 17;32(42):14641-8. doi: 10.1523/JNEUROSCI.2173-12.2012.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / drug effects*
  • Aging / pathology
  • Animals
  • Cisterna Magna* / drug effects
  • Cisterna Magna* / metabolism
  • Cisterna Magna* / pathology
  • Cognition Disorders / metabolism
  • Cognition Disorders / pathology
  • Cognition Disorders / prevention & control*
  • Humans
  • Inflammation Mediators / administration & dosage*
  • Inflammation Mediators / antagonists & inhibitors
  • Injections, Intraventricular
  • Interleukin 1 Receptor Antagonist Protein / administration & dosage*
  • Interleukin-1beta / antagonists & inhibitors*
  • Interleukin-1beta / metabolism
  • Male
  • Postoperative Complications / metabolism
  • Postoperative Complications / pathology
  • Postoperative Complications / prevention & control*
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred F344
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Receptors, Interleukin-1 / metabolism

Substances

  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Receptors, Interleukin-1