Pan Ke, Li Xiaojun, Chen Yan, Zhu Dan, Li Yuping, Tao Guocai, Zuo Zhiyi
Department of Anesthesiology, Southwest Hospital, The Third Military Medical University, Chongqing, China; Department of Anesthesiology, No. 281 Hospital of People's Liberation Army, Hebei, China.
Department of Anesthesiology, Southwest Hospital, The Third Military Medical University, Chongqing, China.
Neuropharmacology. 2016 Dec;111:180-194. doi: 10.1016/j.neuropharm.2016.09.004. Epub 2016 Sep 5.
Postoperative cognitive dysfunction (POCD) is a common complication of elderly patients after surgery. The mechanisms of POCD have not been clarified. Iron accumulation is a feature of neurodegeneration. Recent reports showed that iron content was increased with impaired cognition induced by surgery. We sought to investigate whether iron chelation would attenuate POCD. In this study, male aged (18 months) Sprague-Dawley rats received 100 mg/kg deferoxamine or saline solution (0.9%) for 6 days before exploratory laparotomy. Cognition was evaluated by Morris water maze before and after surgery. Additional rats received deferoxamine or saline were used to determine hippocampal iron content, iron transport-related proteins (transferrin receptor, divalent metal transporter 1, ferroportin 1 and hepcidin), oxidative stress, microglial activation and brain cell apoptosis. It was found that deferoxamine improved postoperative spatial memory in aged rats. Deferoxamine significantly reduced hippocampal iron concentration and ferritin. Surgery increased divalent metal transporter 1 and hepcidin, decreased transferrin receptor and ferroportin 1, and enhanced ferroportin 1 mRNA. However, deferoxamine reversed the changes of these proteins. Furthermore, deferoxamine sharply reduced the hippocampal reactive oxygen species, malondialdehyde concentration and OX-42 that is a marker of microglia, which might reduce postoperative brain cell apoptosis. This study showed that deferoxamine may improve postoperative cognition of aged rats by ameliorating oxidative stress induced by hippocampal iron accumulation, microglial activation and brain cell apoptosis. This study suggests a potential therapeutic method for reducing POCD.
术后认知功能障碍（POCD）是老年患者术后常见的并发症。POCD的发病机制尚未阐明。铁蓄积是神经退行性变的一个特征。最近的报告显示，手术诱导的认知功能受损会导致铁含量增加。我们试图研究铁螯合是否会减轻POCD。在本研究中，18月龄雄性Sprague-Dawley大鼠在剖腹探查术前6天接受100mg/kg去铁胺或生理盐水（0.9%）。通过Morris水迷宫在手术前后评估认知功能。另外使用接受去铁胺或生理盐水的大鼠来测定海马铁含量、铁转运相关蛋白（转铁蛋白受体、二价金属转运体1、铁转运蛋白1和铁调素）、氧化应激、小胶质细胞活化和脑细胞凋亡。结果发现，去铁胺改善了老年大鼠术后的空间记忆。去铁胺显著降低了海马铁浓度和铁蛋白。手术增加了二价金属转运体1和铁调素，降低了转铁蛋白受体和铁转运蛋白1，并增强了铁转运蛋白1的mRNA表达。然而，去铁胺逆转了这些蛋白质的变化。此外，去铁胺大幅降低了海马活性氧、丙二醛浓度以及作为小胶质细胞标志物的OX-42，这可能减少术后脑细胞凋亡。本研究表明，去铁胺可能通过改善海马铁蓄积、小胶质细胞活化和脑细胞凋亡诱导的氧化应激来改善老年大鼠术后的认知功能。本研究提示了一种减少POCD的潜在治疗方法。
