Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction
Statins prevent cognitive impairment after sepsis by reverting neuroinflammation, and microcirculatory/endothelial dysfunction
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DOI：
10.1016/j.bbi.2016.11.006
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发表时间：
2017-02-01
影响因子：
15.1
通讯作者：
Bozza, Fernando A.
中科院分区：
文献类型：
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作者：
Reis, Patricia A.;Alexandre, Pedro C. B.;Bozza, Fernando A.
急性脑功能障碍是败血症患者的常见病，并与死亡率增加和长期神经认知后果有关。记忆和执行功能受损是败血症幸存者的常见发现。尽管神经炎症和血脑屏障功能障碍与急性脑功能障碍及其后果有关，但目前还没有专门的治疗方法来预防败血症后的认知障碍。通过腹腔注射盲肠材料（5 mg/kg, 500 μ L）诱导Swiss Webster小鼠实验性脓毒症。对照组（n = 5/组，每组试验）给予生理盐水500 μ L。支持治疗恢复（生理盐水0.9%,1 mL，亚胺培南30 mg/kg）（注射后6、24、48 h， n = 5-10/组，每次实验），同时或不加服他汀类药物（阿托伐他汀/辛伐他汀20 mg/kg b.w）。分别于诱导后6、24和48 h对动物实施安乐死，进行生化、免疫组织化学和生命体征分析。他汀类药物不能预防脓毒症小鼠的死亡，但幸存者的临床评分较低。在另一组实验中，15天后，粪便上清腹膜败血症的小鼠幸存者出现情境海马和厌恶杏仁核依赖记忆的认知功能障碍，阿托伐他汀/辛伐他汀治疗可预防这种情况。在接受他汀类药物治疗的脓毒症小鼠中，全身和脑组织的促炎细胞因子/趋化因子水平和小胶质细胞的激活水平较低。他汀类药物治疗也降低了脑脂质过氧化和髓过氧化物酶水平。感染性动物的脑血管活体检查显示，功能性毛细血管密度下降，白细胞滚动和粘附增加，血流障碍，他汀类药物治疗可逆转这一现象。此外，他汀类药物治疗可恢复败血症引起的胆碱能血管扩张剂反应。综上所述，这些数据表明，他汀类药物可以逆转败血症期间的微血管功能障碍，减少神经炎症，防止长期认知能力下降。(C) 2016 Elsevier Inc.版权所有。
Acute brain dysfunction is a frequent condition in sepsis patients and is associated with increased mortality and long-term neurocognitive consequences. Impaired memory and executive function are common findings in sepsis survivors. Although neuroinflammation and blood-brain barrier dysfunction have been associated with acute brain dysfunction and its consequences, no specific treatments are available that prevent cognitive impairment after sepsis. Experimental sepsis was induced in Swiss Webster mice by intraperitoneal injection of cecal material (5 mg/kg, 500 mu L). Control groups (n = 5/group each experiment) received 500 mu L of saline. Support therapy recover (saline 0.9%, 1 mL and imipenem 30 mg/kg) were applied (6, 24 and 48 h post injection, n = 5-10/group, each experiment), together or not with additive orally treatment with statins (atorvastatin/simvastatin 20 mg/kg b.w.). Survival rate was monitored at 6, 24 and 48 h. In a setting of experiments, animals were euthanized at 6 and 24 h after induction for biochemical, immunohistochemistry and intravital analysis. Statins did not prevented mortality in septic mice, however survivors presented lower clinical score. At another setting of experiments, after 15 days, mice survivors from fecal supernatant peritoneal sepsis presented cognitive dysfunction for contextual hippocampal and aversive amygdala-dependent memories, which was prevented by atorvastatin/simvastatin treatment. Systemic and brain tissue levels of proinflammatory cytokines/chemokines and activation of microglial were lower in septic mice treated with statins. Brain lipid peroxidation and myeloperoxidase levels were also reduced by statins treatment. Intravital examination of the brain vessels of septic animals revealed decreased functional capillary density and increased rolling and adhesion of leukocytes, and blood flow impairment, which were reversed by treatment with statins. In addition, treatment with statins restored the cholinergic vasodilator response due to sepsis. Taken together, these data demonstrated that statins reverse microvascular dysfunction and reduce neuroinflammation during sepsis, preventing the development of long-term cognitive decline. (C) 2016 Elsevier Inc. All rights reserved.