Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria.
Treatment Reducing Endothelial Activation Protects against Experimental Cerebral Malaria.
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DOI：
10.3390/pathogens11060643
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发表时间：
2022-06-02
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影响因子：
--
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脑型疟疾（CM）是由恶性疟原虫感染引起的最严重的疟疾神经系统并发症。现有的抗疟药物在清除寄生虫方面是有效的，但CM病例的死亡率仍然高达20%。在血管水平，CM的特征是内皮激活和功能障碍。内皮激活的几种生物标志物与CM严重程度和死亡率相关，使脑血管内皮成为预防性治疗的潜在靶点。他汀类药物和血管紧张素II受体阻滞剂（ARB）是分别用于治疗高胆固醇血症和高血压的药物，在其他疾病中显示出内皮保护活性。在这里，我们使用了他汀类药物（阿托伐他汀）和ARB（厄贝沙坦）的组合作为连续治疗，以传统的抗疟药物在小鼠实验模型的CM。我们观察到阿托伐他汀-厄贝沙坦联合给药降低了内皮活化生物标志物的水平，如血管性血友病因子和血管生成素-1。在小鼠出现CM的神经系统体征后，与单独使用抗疟药物治疗相比，联合使用常规抗疟药物治疗使动物的存活率提高了3-4倍，动物数量减少，脑中的血管体积减小。综上所述，我们的研究结果支持抑制内皮活化将大大降低CM相关病理和死亡率的假设。
Cerebral malaria (CM) is the most severe neurological complication of malaria caused by Plasmodium falciparum infection. The available antimalarial drugs are effective at clearing the parasite, but the mortality rate remains as high as 20% of CM cases. At the vascular level, CM is characterized by endothelial activation and dysfunction. Several biomarkers of endothelial activation have been associated with CM severity and mortality, making the brain vascular endothelium a potential target for adjunctive therapies. Statins and Angiotensin II Receptor Blockers (ARBs) are drugs used to treat hypercholesterolemia and hypertension, respectively, that have shown endothelial protective activity in other diseases. Here, we used a combination of a statin (atorvastatin) and an ARB (irbesartan) as adjunctive therapy to conventional antimalarial drugs in a mouse experimental model of CM. We observed that administration of atorvastatin–irbesartan combination decreased the levels of biomarkers of endothelial activation, such as the von Willebrand factor and angiopoietin-1. After mice developed neurological signs of CM, treatment with the combination plus conventional antimalarial drugs increased survival rates of animals 3–4 times compared to treatment with antimalarial drugs alone, with animals presenting lower numbers and smaller hemorrhages in the brain. Taken together, our results support the hypothesis that inhibiting endothelial activation would greatly reduce the CM-associated pathology and mortality.
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DOI：
10.1056/nejmoa1400116
发表时间：
2015-03-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Seydel KB;Kampondeni SD;Valim C;Potchen MJ;Milner DA;Muwalo FW;Birbeck GL;Bradley WG;Fox LL;Glover SJ;Hammond CA;Heyderman RS;Chilingulo CA;Molyneux ME;Taylor TE
通讯作者：
Taylor TE
影响因子：
17.1
作者：
Higgins SJ;Purcell LA;Silver KL;Tran V;Crowley V;Hawkes M;Conroy AL;Opoka RO;Hay JG;Quaggin SE;Thurston G;Liles WC;Kain KC
通讯作者：
Kain KC
影响因子：
3
作者：
Dormoi, Jerome;Briolant, Sebastien;Pradines, Bruno
通讯作者：
Pradines, Bruno
影响因子：
3
作者：
Souraud JB;Briolant S;Dormoi J;Mosnier J;Savini H;Baret E;Amalvict R;Soulard R;Rogier C;Pradines B
通讯作者：
Pradines B
影响因子：
38.9
作者：
Hagiwara, Satoshi;Iwasaka, Hideo;Noguchi, Takayuki
通讯作者：
Noguchi, Takayuki