4-(2-phenyl-5-7-bis(trifluoromethyl)pyrazolo(1-5-a)pyrimidin-3-yl)phenol and Inflammation

High concentrations of palmitic acid in plasma increase both the inflammation associated with obesity and the susceptibility to develop a neurodegenerative event. In the brain, the inflammatory response is mediated by activated microglial cells, which undergo morphological and biochemical changes and can directly affect cell viability. Recent evidence shows that the use of estrogenic compounds can control microglia-induced inflammation with promising results. In this study, we explored the actions of the synthetic steroid tibolone on BV-2 microglia cells stimulated with palmitic acid. Our results demonstrated that tibolone increased cell viability and reduced nuclear fragmentation and the production of reactive oxygen species, as well as preserved mitochondrial membrane potential. These effects were accompanied by reduced nuclear translocation of NF-κB p65, upregulation of neuroglobin, and improved antioxidant defense. Furthermore, estrogen receptor beta (ERβ) inhibition partially dampened tibolone's protective actions in BV-2 cells stimulated with palmitic acid. In conclusion, tibolone protects BV-2 cells by a mechanism involving ERβ and upregulation of neuroglobin.

Topics: Animals; Antioxidants; Cell Line; Cell Nucleus; Cell Shape; Cell Survival; DNA Fragmentation; Estrogen Receptor beta; Inflammation; Membrane Potential, Mitochondrial; Mice; Microglia; Mitochondria; Neuroglobin; Neuroprotective Agents; Nitriles; Norpregnenes; Oxidation-Reduction; Oxidative Stress; Palmitic Acid; Pyrazoles; Pyrimidines; Receptors, Androgen; Transcription Factor RelA

Estrogen was reported to protect against obesity, however the mechanism remains unclear. We aimed to investigate the impact of 17β-estradiol (17β-E2) on triglyceride metabolism in adipocytes with or without lipopolysacchride (LPS) stimulating, providing novel potential mechanism for estrogen action.. 3T3-L1 adipocytes were cultured and differentiated into mature adipocytes in vitro. The differentiated 3T3-L1 cells were divided into six groups: (i) control group, treated with 0.1% DMSO alone; (ii) 17β-E2 group, treated with 1, 0.1, or 0.001 μM 17β-E2 for 48 h; (iii) 17β-E2 plus MPP group, pre-treated with 10 μM MPP (a selective ERα receptor inhibitor) for 1 h, then incubated with 1 μM 17β-E2 for 48 h; (iv) 17β-E2 plus PHTPP group, pre-treated with 10 μM PHTPP (a selective ERβ receptor inhibitor), then incubated with 1 μM 17β-E2 for 48 h; (v) LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 0.1% DMSO alone for 48 h; (vi) 17β-E2 plus LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 1 μM 17β-E2 for 48 h. The levels of triglyceride and adipose triglyceride lipase (ATGL) in differentiated 3T3-L1 cells and the concentrations of interleukin-6 (IL-6) in culture medium were measured.. Comparing with control group, 1 μM and 0.1 μM 17β-E2 decreased the intracellular TG levels by about 20% and 10% respectively (all P < 0.05). The triglyceride-lowing effect of 17β-E2 in differentiated 3T3-L1 cells was abolished by ERα antagonist MPP but not ERβ antagonist PHTPP. Comparing with control group, the IL-6 levels were significantly higher in the culture medium of the cultured differentiated 3T3-L1 cells in LPS group and 17β-E2 + LPS group (all P < 0.05). And, the IL-6 levels were similar in LPS group and 17β-E2 + LPS group (P > 0.05). There was no significant difference in the triglyceride contents of differentiated 3T3-L1 cells among control group, LPS group and 17β-E2 + LPS group (all P > 0.05). ATGL expression in 17β-E2 group was significantly higher than control group (P < 0.05), which was abolished by ERα antagonist MPP or LPS.. 17β-E2 increased ATGL expression and lowered triglycerides in adipocytes but not in LPS stimulated adipocytes via estrogen ERα.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Differentiation; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Gene Expression Regulation; Inflammation; Interleukin-6; Lipase; Lipid Metabolism; Lipopolysaccharides; Mice; Piperidines; Pyrazoles; Pyrimidines; Triglycerides