Abstract
Gracilins are diterpenes derivative, isolated from the marine sponge Spongionella gracilis. Natural gracilins and synthetic derivatives have shown antioxidant, immunosuppressive, and neuroprotective capacities related to the affinity for cyclophilins. The aim of this work was to study anti-inflammatory and immunosuppressive pathways modulated by gracilin L and two synthetic analogues, compound 1 and 2, on a cellular model of inflammation. In this way, the murine BV2 microglia cell line was used. To carry out the experiments, microglia cells were pre-treated with compounds for 1 h and then stimulated with lipopolysaccharide for 24 h to determine reactive oxygen species production, mitochondrial membrane potential, the release of nitric oxide, interleukin-6 and tumor necrosis factor-α and the expression of Nuclear factor-erythroid 2-related factor 2, Nuclear Factor-κB, the inducible nitric oxide synthase, and the cyclophilin A. Finally, a co-culture of neuron SH-SY5Y and microglia BV2 cells was used to check the neuroprotective effect of these compounds. Cyclosporine A was used as a control of effect. The compounds were able to decrease inflammatory mediators, the expression of inflammatory target proteins as well as they activated anti-oxidative mechanism upon inflammatory conditions. For this reason, natural and synthetic gracilins could be interesting for developing anti-inflammatory drugs.
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Acknowledgements
This work could not have been done without the invaluable collaboration of Dr. Daniel Romo group from the Department of Chemistry and Biochemistry, Baylor University, TX (United States).
Funding
The research leading to these results has received funding from the following FEDER cofunded-Grants. From Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia, 2017 GRC GI-1682 (ED431C 2017/01). From CDTI and Technological Funds, supported by Ministerio de Economía, Industria y Competitividad, AGL2016-78728-R (AEI/FEDER, UE), ISCIII/PI16/01830 and RTC-2016-5507-2, ITC-20161072. From European Union POCTEP 0161-Nanoeaters -1-E-1, Interreg AlertoxNet EAPA-317-2016, Interreg Agritox EAPA-998-2018, and H2020 778069-EMERTOX. Sandra Gegunde was supported by a fellowship from FIDIS, Spain.
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Conceptualization: Sandra Gegunde and Amparo Alfonso. Methodology and formal analysis: Sandra Gegunde and Rebeca Alvariño. Validation: Eva Alonso. Writing-Original Draft Preparation: Sandra Gegunde. Writing-Review and Editing: Amparo Alfonso and Luis Botana. Supervision: Amparo Alfonso. Funding’s acquisitions: Amparo Alfonso and Luis Botana.
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Gegunde, S., Alfonso, A., Alonso, E. et al. Gracilin-Derivatives as Lead Compounds for Anti-inflammatory Effects. Cell Mol Neurobiol 40, 603–615 (2020). https://doi.org/10.1007/s10571-019-00758-5
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DOI: https://doi.org/10.1007/s10571-019-00758-5