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.

Figure 1.

Inset, Locomotion during the conditioning session was nearly 100% and did not differ between any of the groups. A, Laparotomy 4 d before contextual fear conditioning produced a significant memory deficit for hippocampal-dependent contextual memory in aged, but not adult, rats. A sham operation did not produce any memory impairments. B, There was no effect of surgery, regardless of age, on the hippocampal-independent auditory-cued test. C, Laparotomy, regardless of age, produced a significant reduction in percentage of body weight compared with sham-operated groups. **p < 0.01; ****p < 0.0001.

Figure 2.

Hippocampal IL-1β protein levels were significantly elevated 24 h (A) and 4 d (B) after laparotomy in aged, but not adult, rats. A sham operation did not produce an elevation in IL-1β at either time point, regardless of age. **p < 0.01.

Figure 3.

Inset, Locomotion during the conditioning session was nearly 100% and did not differ between any of the groups. A, A single icm injection of hIL-1RA (112 μg) administered at the time of surgery prevented the surgery-induced memory consolidation impairments in aged rats 4 d later. The same dose of hIL-1RA administered intraperitoneally was not effective, as freezing levels did not differ from those of the vehicle-treated group. B, Auditory-cued memory was unaffected by surgery or hIL-1RA treatment. C, Each of the surgical groups, regardless of treatment or route of administration, had lower body weights compared with the sham-operated group. *p < 0.05; **p < 0.01.

Figure 4.

A, A single icm injection of hIL-1RA (112 μg) administered at the time of surgery prevented surgery-induced IL-1β protein elevations in the hippocampus in aged rats 4 d later. The same dose of hIL-1RA administered intraperitoneally was not effective, as IL-1β levels did not differ from those of the vehicle-treated group. B, IL-1β protein levels in the liver 4 d after laparotomy were not different across groups. *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 5.

A, In the hippocampus, aged rats that received a single icm injection of hIL-1RA (112 μg) at the time of surgery continued to express significantly elevated levels of hIL-1RA compared with background (vehicle) and intraperitoneal IL-1RA-administered levels 4 d later. intraperitoneal hIL-1RA levels were no different from background levels at this time point. B, In the liver, regardless of the route of administration, aged rats that received a single injection of hIL-1RA (112 μg) at the time of surgery exhibited levels of hIL-1RA no different from background (vehicle) levels 4 d later. C, In the serum, hIL-1RA was highly and equally expressed 1 h after both routes of administration. At 3 h, hIL-1RA expression levels dropped precipitously (note scale change), with icm-administered levels significantly higher than intraperitoneal-administered levels. At 24 h, hIL-1RA expression levels dropped precipitously again (note scale change). At this time point, icm-administered levels continued to be expressed significantly higher than intraperitoneal-administered levels. At 4 d, hIL-1RA expression levels were no longer different than background (vehicle) levels. **p < 0.01; ****p < 0.0001.