Identifying adjunctive therapy in the experimental model of malaria to improve cerebral malaria outcomes

摘要 疟疾仍然是一个巨大的公共卫生挑战，它抵制了世界范围内的控制努力。有些人 感染恶性疟原虫的人会患上脑型疟疾(CM)，这与高 尽管使用了抗疟疾治疗，但发病率和死亡率仍然很高。到目前为止，还没有有效的辅助疗法 可用。由于脑肿胀最近被确定为CM的主要死亡原因，我们建议测试二甲基甲基 富马酸(DMF)对实验性脑疟疾小鼠神经炎症的调节作用 组织病理学和神经成像技术，以确定其保护机制。初步数据 证明DMF在ECM中提供了生存优势。重要的是，DMF是FDA批准的其他 神经炎性疾病，因此有可能被重新用于CM。我们的长期目标是确定 在临床前模型中，潜在的辅助治疗可以减少脑肿胀并提高存活率，以提供 为未来的临床试验奠定基础，并最终改善CM的结果。

ABSTRACT Malaria remains a great public health challenge that has resisted worldwide control efforts. Some individuals who are infected with Plasmodium falciparum develop cerebral malaria (CM), which is associated with high morbidity and mortality despite the use of antimalarial therapy. To date, no effective adjunctive therapy is available. As brain swelling was recently identified as the main cause of death in CM, we propose to test dimethyl fumarate (DMF) to modulate neuroinflammation in an experimental cerebral malaria mouse model using histopathological and neuroimaging techniques to define its mechanisms of protection. The preliminary data demonstrate that DMF provides a survival advantage in ECM. Importantly, DMF is FDA-approved for other neuroinflammatory conditions and thus could potentially be repurposed for CM. Our long-term goal is to identify potential adjunctive therapies that reduce brain swelling and increase survival in a pre-clinical model to provide a foundation for future clinical trials and ultimately improve the outcomes of CM.