Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China.
Department of Anesthesiology, Jinling Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210003, P.R. China.
Mol Med Rep. 2018 Mar;17(3):3845-3852. doi: 10.3892/mmr.2018.8370. Epub 2018 Jan 2.
Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterized by varying degrees of cognitive functional decline in patients following major surgery. Inflammation and a dysregulated innate immune system exert broad effects in the periphery and central nervous system, yet the mechanisms underlying POCD remain poorly understood and without effective therapy. It has been reported that modulation of the dysregulated inflammatory response with low‑dose lipopolysaccharide (LPS) preconditioning, a phenomenon additionally referred to as endotoxin tolerance, has the potential to reduce neuroinflammation, blood‑brain barrier disruption, and cognitive impairment in a number of disease states. Therefore, it was hypothesized that endotoxin tolerance induced by LPS preconditioning may protect against surgery‑induced cognitive impairment in aging mice. Using a mouse model of surgery‑induced cognitive decline, the present study demonstrated that exploratory laparotomy caused a significant impairment in hippocampal‑dependent memory. Notably, one application of low‑dose LPS preconditioning at 24 h prior to surgery improved the cognitive impairment and abolished the signs of neuroinflammation in the hippocampus following surgery. However, LPS injection at 6 h or immediately prior to surgery did not confer such beneficial effects, suggesting that the effects of LPS‑induced endotoxin tolerance may depend on the time of application. In conclusion, the results of the present study suggested that low‑dose LPS preconditioning may markedly alleviate surgery‑induced neuroinflammation and cognitive impairment in aging mice, which may provide a novel approach to preventing POCD and, potentially, other forms of memory impairment.
术后认知功能障碍（POCD）是一种临床综合征，其特征是患者在接受大手术后出现不同程度的认知功能下降。炎症和失调的固有免疫系统在周围和中枢神经系统中产生广泛的影响，但 POCD 的发病机制仍知之甚少，且尚无有效的治疗方法。据报道，通过低剂量脂多糖（LPS）预处理调节失调的炎症反应，这种现象也被称为内毒素耐受，具有减轻神经炎症、血脑屏障破坏和认知障碍的潜力，在多种疾病状态下均如此。因此，有人假设 LPS 预处理诱导的内毒素耐受可能会防止衰老小鼠手术引起的认知障碍。本研究采用手术引起认知能力下降的小鼠模型，证明了剖腹手术可导致海马依赖性记忆明显受损。值得注意的是，手术前 24 小时应用低剂量 LPS 预处理一次可改善认知障碍，并消除手术后海马区的神经炎症迹象。然而，在手术前 6 小时或立即注射 LPS 则没有这种有益效果，这表明 LPS 诱导的内毒素耐受的作用可能取决于应用时间。综上所述，本研究结果表明，低剂量 LPS 预处理可能显著减轻衰老小鼠手术引起的神经炎症和认知障碍，这可能为预防 POCD 及其他形式的记忆障碍提供一种新方法。
