Edaravone at high concentrations attenuates cognitive dysfunctions induced by abdominal surgery under general anesthesia in aged mice
Edaravone at high concentrations attenuates cognitive dysfunctions induced by abdominal surgery under general anesthesia in aged mice
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高浓度依达拉奉可减轻老年小鼠全身麻醉下腹部手术引起的认知功能障碍
DOI：
10.1007/s11011-019-00532-y
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发表时间：
2020-01
影响因子：
3.6
通讯作者：
Cui Wei
中科院分区：
文献类型：
--
作者：
Zhou Yiying;Wu Xiang;Ye Luying;Bai Yujing;Zhang Hui;Xuan Zhenquan;Feng Yi;Zhang Panpan;Chen Yi;Yan Yushan;Zhu Binbin;Cui Wei
术后认知功能障碍（POCD）是影响老年患者术后的常见神经系统疾病。不幸的是，尚未发现有效的治疗这种疾病的方法。据报道，临床使用的自由基清除剂依达拉奉（3 mg/kg）可预防成年啮齿动物中手术和脂多糖联合诱导的神经炎症。然而，我们发现依达拉奉在如此低的浓度下不能抑制老年小鼠的POCD。相反，33.2 mg/kg依达拉奉显著预防了14月龄小鼠在异氟烷全身麻醉下接受腹部手术后的识别和空间认知功能障碍。此外，依达拉奉可显著预防老年小鼠腹部手术诱导的肿瘤坏死因子-α（TNF-α）、白细胞介素-1 β（IL-1 β）和白细胞介素-6（IL-6）升高。依达拉奉还可以减少手术小鼠海马区胶质纤维酸性蛋白（GFAP）和离子钙结合衔接分子-1（Iba-1）阳性面积，表明依达拉奉可能抑制手术诱导的小胶质细胞和星形胶质细胞的过度激活。此外，依达拉奉显著增加PSD-95和pSer 9-糖原合成酶激酶-3 β（pSer 9-GSK 3 β）的表达，如Western印迹分析所示。依达拉奉组小鼠乙酰胆碱酯酶（AChE）活性降低。以上结果提示，高浓度依达拉奉可能通过减轻神经炎症反应、增加突触蛋白和增强胆碱能传递等途径抑制手术诱导的老年动物认知功能障碍，为依达拉奉治疗POCD提供了进一步的支持。
Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3 beta (pSer9-GSK3 beta) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD.
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