Improvement of the efficacy of dihydroartemisinin with atorvastatin in an experimental cerebral malaria murine model
Improvement of the efficacy of dihydroartemisinin with atorvastatin in an experimental cerebral malaria murine model
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DOI：
10.1186/1475-2875-12-302
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发表时间：
2013-08-30
期刊：
影响因子：
3
通讯作者：
Pradines, Bruno
中科院分区：
文献类型：
--
作者：
Dormoi, Jerome;Briolant, Sebastien;Pradines, Bruno
背景：疟疾的医疗护理是临床急症，因为它可能发展为重症疟疾，具有很高的并发症和死亡风险。恶性疟原虫感染的主要并发症之一是脑型疟疾（CM），它每年在全世界造成至少17.5万人死亡，并具有长期的神经系统后遗症。此外，CM的治疗只是部分有效。目前已知他汀类药物具有抗炎作用、减轻败血症和神经保护作用。在体外，阿托伐他汀（AVA）具有抗疟疾活性，并能提高奎宁（QN）、甲氟喹（MQ）和双氢青蒿素（DHA）的活性。目的：本研究有两个目的。首先，在C57BL6/N小鼠实验性脑型疟疾（ECM）模型中，研究了AVA通过提高CM存活率和降低CM体征来增强DHA功效的能力。其次，在D6和D10时，对DHA治疗的小鼠和未治疗的小鼠进行炎症生物标志物评估，这些小鼠在D12之前迅速出现CM临床症状并死亡。两个实验均采用40mg /kg AVA联合3mg /kg DHA腹腔注射7天的方法。结果：AVA与DHA联合治疗方案可显著延缓小鼠死亡，并对CM症状的发作和寄生虫血症水平有影响。生物标志物的评估强调了治疗小鼠和对照组之间的五种已知在趋化性中起作用的细胞因子和趋化因子（Eotaxin-CCL11, IL-13, LIX-CXCL5， MIP1b-CCL4和MIP2）的显著差异。结论：DHA和AVA联合治疗似乎是一种有效的改善小鼠生存的治疗方案，但对细胞因子调节的效果较差，而细胞因子调节与预防CM有关。这些结果要求进行临床试验，将AVA作为抗疟疾治疗的辅助剂，特别是与以青蒿素为基础的联合治疗一起，用于治疗或预防CM。
Background: The medical care of malaria is a clinical emergency because it may develop into severe malaria, which has a high risk of complications and death. One of the major complications of Plasmodium falciparum infections is cerebral malaria (CM), which is responsible for at least 175,000 deaths worldwide each year and has long-term neurological sequelae. Moreover, treatment for CM is only partially effective. Statins are now known to have anti-inflammatory action, to attenuate sepsis and to have neuroprotective effects. In vitro, atorvastatin (AVA) has an anti-malarial activity and has improved the activity of quinine (QN), mefloquine (MQ), and dihydroartemisinin (DHA).Objectives: This study had two objectives. First, the ability of AVA to enhance DHA efficacy by improving the survival rate for CM and also decreasing signs of CM was evaluated in a murine model of experimental cerebral malaria (ECM), which was designed in C57BL6/N mice. Second, the inflammatory biomarkers were assessed at D6 and D10 in mice treated by DHA and in untreated mice in which clinical signs of CM appear rapidly and death occurs before D12. Both experiments were designed with seven days of treatment with 40 mg/kg AVA combined with five days of 3 mg/kg DHA administered intraperitoneally.Results: AVA in combination with DHA in a therapeutic scheme leads to a significant delay in mouse death, and it has an effect on the onset of CM symptoms and on the level of parasitaemia. Evaluation of the biomarkers highlights the significant difference between treated and control mice for five cytokines and chemokines (Eotaxin-CCL11, IL-13, LIX-CXCL5, MIP1b-CCL4 and MIP2) that are known to have a role in chemotaxis.Conclusions: The combination of DHA and AVA seems to be effective as a therapeutic scheme for improving mouse survival but less effective for cytokine modulation, which is associated with protection against CM. These results call for clinical trials of AVA as an adjuvant with anti-malarial therapy, especially with artemisinin-based combination therapy, in CM treatment or prevention.