Tobacco-derived 4R-cembranoid protects neuronal cells from oxygen-glucose deprivation by modulating microglial cell activation
Fu, Hefei et al. “4R-cembranoid protects neuronal cells from oxygen-glucose deprivation by modulating microglial cell activation.” Brain research bulletin vol. 179 (2022): 74-82. doi:10.1016/j.brainresbull.2021.12.007
In the search for novel compounds to treat neurodegenerative diseases, we found that 4R-cembranoid, an extract from tobacco leaves, may be a lead compound with anti-inflammatory and neuroprotective properties. 4R belongs to the family of cembranoids containing 14-carbon cembrane ring cyclic diterpenoids (Hann et al. 1998; Ferchmin et al. 2001). 4R is a stable and highly lipophilic small molecule (MW: 306) that penetrates the blood–brain barrier (BBB) and remains in the brain (Velez-Carrasco et al. 2015). 4R has been reported to exert neuroprotective and anti-inflammatory effects on brain ischemia-, NMDA-, 6-OHDA- or organophosphorus insecticide-induced injury (Martins et al. 2015; Ferchmin et al. 2005; Hu et al. 2017; Ferchmin et al. 2015; Ferchmin et al. 2014; Eterovic et al. 2013; Eterovic et al. 2011). Studies have also shown that activation of the PI3-kinase/Akt cascade and inhibition of ICAM-1, VCAM-1 and NF-κB activities are involved in the neuroprotective and anti-inflammatory effects of 4R (Martins et al. 2015; Ferchmin et al. 2005). The therapeutic effects of 4R on both in vitro and in vivo models of ischemic stroke and Parkinson’s disease are associated with anti-inflammatory actions in brain endothelial cells (Hu et al. 2017; Martins et al. 2015). This knowledge has inspired us to hypothesize that 4R may also exert anti-inflammatory effects on microglia by modulating M1/M2 phenotypes to protect neurons from injury after ischemia or inflammation.
Fu, Hefei et al. “4R-cembranoid protects neuronal cells from oxygen-glucose deprivation by modulating microglial cell activation.” Brain research bulletin vol. 179 (2022): 74-82. doi:10.1016/j.brainresbull.2021.12.007
Abstract: As major immune responsive cells in the central nervous system (CNS), activated microglia can present pro-inflammatory M1 phenotype aggravating the neuronal injury or anti-inflammatory M2 phenotype providing neuroprotection and promoting neuronal survival in neurodegenerative diseases. In this study, we demonstrated that a compound, 4R-cembranoid (4R, 1S, 2E, 4R, 6R,-7E, 11E-2, 7, 11-cembratriene-4, 6-diol cembranoids) promoted M2 phenotype while attenuated M1 phenotype in N9 cells, a microglial cell line. Following Lipopolysaccharides (LPS) or Oxygen-glucose deprivation (OGD) treatment, the N9 cells treated by 1 μM 4R showed an increased Arginase-1 (Arg1, a M2 marker) expression and a reduced inducible nitric oxide synthase (iNOS, M1 marker) expression. In addition, the conditioned medium of 4R-treated post-OGD N9 cells protected neuro2a cells, a neuronal cell line, from OGD-induced injury. The viability of neuro2a cells in OGD condition was increased by 54.5% after treated with the conditioned medium of 4R-treated post-OGD N9 cells. Furthermore, we demonstrated the protective mechanism of 4R was associated with a decreased TNF-α release and an increased IL-10 release from N9 cells. In conclusion, our study demonstrated that the neuroprotective effects of 4R were through the regulation of microglial activation by promoting the protective M2 activation and inhibiting the damaging M1 activation. Therefore, the findings of this study suggest that 4R could be a promising lead structure for the development of drugs for the treatment of ischemic stroke and other neurodegenerative diseases with an inflammatory component involved.
