Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, China.
J Neurochem. 2022 Aug;162(3):290-304. doi: 10.1111/jnc.15620. Epub 2022 May 21.
Alzheimer's disease (AD) remains a leading cause of dementia and no therapy that reverses underlying neurodegeneration is available. Recent studies suggest the protective role of artemisinin, an antimalarial drug, in neurological disorders. In this study, we investigated the therapeutic potential of artesunate, a water-soluble derivative of artemisinin, on amyloid-beta (Aβ)-treated challenged microglial BV-2, neuronal N2a cells, and the amyloid precursor protein/presenilin (APP/PS1) mice model. We found that Aβ significantly induced multiple AD-related phenotypes, including increased expression/production of pro-inflammatory cytokines from microglial cells, enhanced cellular and mitochondrial production of reactive oxygen species, promoted mitochondrial fission, inhibited mitochondrial fusion, suppressed mitophagy or biogenesis in both cell types, stimulated apoptosis of neuronal cells, and microglia-induced killing of neurons. All these in vitro phenotypes were attenuated by artesunate. In addition, the over-expression of the mitochondrial fission protein Drp-1, or down-regulation of the mitochondrial fusion protein OPA-1 both reduced the therapeutic benefits of artesunate. Artesunate also alleviated AD phenotypes in APP/PS1 mice, reducing Aβ deposition, and reversing deficits in memory and learning. Artesunate protects neuronal and microglial cells from AD pathology, both in vitro and in vivo. Maintaining mitochondrial dynamics and simultaneously targeting multiple AD pathogenic mechanisms are associated with the protective effects of artesunate. Consequently, artesunate may become a promising therapeutic for AD.
阿尔茨海默病（AD）仍然是痴呆症的主要原因，目前尚无可逆转潜在神经退行性病变的治疗方法。最近的研究表明，抗疟药物青蒿素在神经疾病中具有保护作用。在这项研究中，我们研究了青蒿琥酯（青蒿素的水溶性衍生物）在淀粉样蛋白-β（Aβ）处理挑战的小神经胶质 BV-2 细胞、神经元 N2a 细胞和淀粉样前体蛋白/早老素（APP/PS1）小鼠模型中的治疗潜力。我们发现 Aβ 显著诱导了多种 AD 相关表型，包括小神经胶质细胞中促炎细胞因子的表达/产生增加、细胞和线粒体中活性氧的产生增强、促进线粒体裂变、抑制线粒体融合、抑制两种细胞类型中的自噬或生物发生、刺激神经元细胞凋亡以及小神经胶质细胞诱导神经元细胞死亡。青蒿琥酯均可减轻所有这些体外表型。此外，线粒体裂变蛋白 Drp-1 的过表达或线粒体融合蛋白 OPA-1 的下调均降低了青蒿琥酯的治疗效果。青蒿琥酯还减轻了 APP/PS1 小鼠的 AD 表型，减少了 Aβ 沉积，并逆转了记忆和学习缺陷。青蒿琥酯可保护神经元和小神经胶质细胞免受 AD 病理影响，在体外和体内均有作用。维持线粒体动力学并同时针对多种 AD 发病机制与青蒿琥酯的保护作用有关。因此，青蒿琥酯可能成为治疗 AD 的一种有前途的药物。
