A Novel Carbon Monoxide-Releasing Molecule Fully Protects Mice from Severe Malaria
A Novel Carbon Monoxide-Releasing Molecule Fully Protects Mice from Severe Malaria
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DOI：
10.1128/aac.05571-11
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发表时间：
2012-03-01
影响因子：
4.9
通讯作者：
Pamplona, Ana
中科院分区：
文献类型：
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作者：
Pena, Ana C.;Penacho, Nuno;Pamplona, Ana
严重形式的疟疾感染，如脑型疟疾(CM)和急性肺损伤(ALI)，主要由顶复合体寄生虫恶性疟原虫引起。奎宁或青蒿素衍生物的初级治疗通常对控制恶性疟原虫寄生虫病有效，但CM和其他形式的严重疟疾的死亡率仍然高得令人无法接受。在此，我们报道了一种新型的一氧化碳释放分子(CO-RM；ALF492)的设计和合成，该分子能够完全保护小鼠免受实验性CM(ECM)和ALI的攻击。ALF492可以在体内控制一氧化碳的输送，而不会影响血红蛋白的氧气运输，这是一氧化碳吸入治疗的主要限制。这种保护作用是一氧化碳依赖的，并诱导了血红素加氧酶-1的表达，这有助于观察到的保护作用。重要的是，当与抗疟疾药物青蒿琥酯联合使用时，ALF492是ECM的有效辅助和辅助治疗，在严重疾病发作后提供保护。这项研究为可能使用ALF492等CO-RMS作为严重形式疟疾感染的辅助/辅助治疗铺平了道路。
Severe forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasite Plasmodium falciparum. Primary therapy with quinine or artemisinin derivatives is generally effective in controlling P. falciparum parasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO delivery in vivo without affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection.