Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats.
Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats.
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DOI：
10.1523/jneurosci.2173-12.2012
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发表时间：
2012-10-17
期刊：
影响因子：
--
通讯作者：
Maier SF
中科院分区：
文献类型：
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作者：
Barrientos RM;Hein AM;Frank MG;Watkins LR;Maier SF
为探讨促炎性细胞因子白介素1β(IL-1β)在老年大鼠术后认知功能障碍中的作用，我们在成年(3mo)和老年(24mo)F344/BN大鼠上模拟开腹手术。我们证明，手术后4天，老年大鼠对依赖于海马体的情景恐惧条件反射任务的记忆巩固明显受损，但年轻大鼠没有。在这两个年龄组中，开腹手术都不会扰乱对海马区独立听觉线索的恐惧记忆。老年动物术后1天和4天的海马区IL-1β水平升高与海马区依赖记忆损害程度呈平行关系。这些发现支持了我们之前的大量研究，这些研究表明，在外围免疫挑战之后，老年动物更容易出现认知能力下降。此外，我们还证明，手术时脑池内一次性注射白介素1受体拮抗剂(IL-1RA；112微克)足以阻断行为缺陷和神经炎性反应。外周注射相同剂量的IL-1RA未能起到保护作用。这些数据为中枢而不是外周IL-1β在POCD中的特定作用提供了强有力的支持。此外，IL-1RA在大脑中的长期存在(4天)比在血液中(24小时)的存在时间更长，这突显了脑池内给药的治疗价值。
To investigate the role of the pro-inflammatory cytokine interleukin-1beta (IL-1β) in post-operative cognitive dysfunction (POCD) in aged rats, we employed laparotomy to mimic human abdominal surgery in adult (3 mo) and aged (24 mo) 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 days following 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 days following surgery. These findings support our substantial line of previous research showing that aged animals are more vulnerable to cognitive decline following a peripheral immune challenge. In addition, we demonstrated that a single intracisternal administration of interleukin-1 receptor antagonist (IL-1RA; 112ug) 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 days) compared to in the blood (<24 hr) underscores the value of intracisternal administration of IL-1RA for therapeutic purposes.