2. Academic Validation
  3. Cannabidiol-dihydroartemisinin conjugates for ameliorating neuroinflammation with reduced cytotoxicity

Cannabidiol-dihydroartemisinin conjugates for ameliorating neuroinflammation with reduced cytotoxicity

  • Bioorg Med Chem. 2021 Jun 1:39:116131. doi: 10.1016/j.bmc.2021.116131.
Fanfan Wang 1,  Ming Li 2,  Cong Lin 3,  Sha Jin 4,  Hongyuan Li 3,  Yuyuan Lu 4,  Hengshan Wang 5,  Hongshuang Wang 6,  Xiaohui Wang 7
Affiliations

Affiliations

  • 1 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
  • 2 Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, China.
  • 3 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
  • 4 State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
  • 5 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: [email protected].
  • 6 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China. Electronic address: [email protected].
  • 7 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China. Electronic address: [email protected].
PMID: 33852975 DOI: 10.1016/j.bmc.2021.116131
Abstract

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.

Keywords

Anti-inflammatory; Cannabidiol; Dihydroartemisinin; Drug-drug interaction; Lipopolysaccharides (LPS).

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