Background: Berberine is a promising natural drug that has a potential therapeutic effect on neurodegenerative diseases. Objectives: Using U251 cells in vitro, we investigated whether berberine exerts its neuroprotective effect via regulation of CYP2J2. Method: After pretreatment with increasing concentrations (1, 3, and 10 μmol/L) of berberine for 0.5 h, U251 cells were stimulated with 1 μg/mL of lipopolysaccharide (LPS). Cell viability was measured 24 h later using a CCK8 kit. mRNA and protein levels of CYP2J2 and peroxisome proliferator-activated receptor alpha (PPARα) were measured by quantitative real-time-polymerase chain reaction and western blotting, respectively, after 24 h of exposure to 1, 3, or 10 μmol/L berberine. Fluorescence immunocytochemistry was also used to evaluate PPARα protein expression after treatment of U251 cells with 10-μmol/L berberine for 24 h. Transient transfection (cotransfection with the plasmid of PPARα- and RXRα-containing) followed by luciferase and chromatin immunoprecipitation assays was used to elucidate the molecular mechanism underlying the observed effects. Results: Compared to the control, LPS-induced U251 cell death was attenuated by berberine in a dose-dependent manner. After 24 h, cell viability was found to be 52.3% (p < 0.05), 66.2% (p < 0.01), and 70.9% (p < 0.001) using 1, 3, and 10 μmol/L berberine treatment, respectively. At these concentrations, berberine increased the CYP2J2 mRNA levels by 1.31-fold (p < 0.05), 1.48-fold (p < 0.01), and 1.88-fold (p < 0.01), respectively, and increased the PPARα mRNA levels 1.17-fold (p < 0.05), 1.29-fold (p < 0.05), and 1.53-fold (p < 0.01), respectively, compared with the respective control groups. In addition, the CYP2J2 and PPARα protein level was also significantly upregulated in U251 cells by berberine (concentrations in 1, 3, and 10 μmol/L) in a dose-dependent manner, compared with the respective control groups. Further investigation indicated that berberine enhances the heterodimerization of PPARα and RXRα, which together bind to the CYP2J2 promoter to induce the expression of CYP2J2 in U251 cells. Conclusion: Upon exposure of U251 cells to berberine, CYP2J2 expression is induced as a result of PPARα stimulation, resulting in a neuroprotective effect.

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