Cannabidiol-dihydroartemisinin conjugates for ameliorating neuroinflammation with reduced cytotoxicity
Cannabidiol-dihydroartemisinin conjugates for ameliorating neuroinflammation with reduced cytotoxicity
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大麻二酚-二氢青蒿素缀合物用于改善神经炎症并降低细胞毒性
DOI：
10.1016/j.bmc.2021.116131
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Xiaohui Wang
中科院分区：
文献类型：
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作者：
Fanfan Wang;Ming Li;Cong Lin;Sha Jin;Hongyuan Li;Yuyuan Lu;Hengshan Wang;Hongshuang Wang;Xiaohui Wang
大麻二酚（CBD）和二氢青蒿素（DHA）可以减轻神经炎症反应。然而，它们表现出细胞毒性，这严重限制了它们的治疗窗口。因此，非常需要开发安全性更高的神经保护剂。药物-药物缀合物是一种提高治疗指数的新兴方法。在此，进行了 CBD-DHA 缀合物的开发、合成和药理学表征。同时，还对 CBD 和 DHA 作为单独实体的组合进行了定量分析，以便与 CBD-DHA 缀合物进行直接比较。在这项研究中，使用 BV-2 小胶质细胞系来模拟原代小胶质细胞，并评估了 CBD、DHA、CBD 和 DHA 的组合以及 CBD-DHA 缀合物对 LPS 激活的信号分子和促炎因子的影响。 CBD 和 DHA 在抑制 LPS 诱导的一氧化氮 (NO) 产生方面的相互作用被发现是相加的。相反，DHA 被发现与 CBD 协同抑制 BV-2 细胞活力，这意味着 CBD 和 DHA 的组合增强了它们的细胞毒性。 CBD-DHA 缀合物 C3D 消除了与单一 CBD/DHA 使用相关的细胞毒性，而不会显着损害抗神经炎症活性。 C3D 在抑制 LPS 诱导的 NO 以及 iNOS 和 IL-1β mRNA 方面比 C2D 和 C4D 更有效，这意味着接头长度对于 CBD-DHA 缀合物的抗炎活性至关重要。进一步的信号传导特征表明，C3D 抑制 BV-2 细胞中 LPS 诱导的 NF-κB 但不抑制 MAPK 激活，从而阻断 LPS 诱导的神经炎症。这项工作提供了一个很好的例子，表明与传统的组合策略相比，药物-药物结合方法可以通过增加最大耐受浓度/剂量来提高治疗指数。
Cannabidiol (CBD) and dihydroartemisinin (DHA) can alleviate neuroinflammatory responses. However, they show cytotoxicity, which severely limits their therapeutic windows. Therefore, there is a great need to develop neuroprotective agents with improved safety. Drug-drug conjugate is an emerging approach for enhancing therapeutic index. Herein, the development, synthesis, and the pharmacological characterization of CBD-DHA conjugates were performed. Meanwhile, the combination of CBD and DHA as separate entities was also quantitatively analyzed for direct comparison with CBD-DHA conjugates. In this study, BV-2 microglial cell line was used to mimic primary microglia and the effects of CBD, DHA, the combination of CBD and DHA, as well as CBD-DHA conjugates on LPS-activated signaling molecules and pro-inflammatory factors were assessed. The interaction of CBD and DHA in inhibiting LPS-induced nitric oxide (NO) production was found to be additive. In contrast, DHA was found to synergize with CBD in inhibiting BV-2 cellular viability which implies that the combination of CBD and DHA amplifies their cytotoxicity. CBD-DHA conjugate C3D eliminated the cytotoxicity associated with single CBD/DHA use without significantly compromising the anti-neuroinflammation activity. C3D was more potent than C2D and C4D in inhibiting LPS-induced NO and mRNAs of iNOS and IL-1β, which implies that the linker length is critical for CBD-DHA conjugates’ anti-inflammatory activities. Further signaling characterizations showed that C3D inhibited LPS-induced NF-κB but not MAPKs activation in BV-2 cells, therefore blocking LPS-induced neuroinflammation. This work provides a good example that conjugated drug-drug approach may improve the therapeutic index by increasing the maximum tolerated concentration/dose compared to traditional combination strategy.