Synthesis of Naringenin and Senecioic Acid Ester Derivatives and Biological Evaluation of the Astrocyte Antioxidant Mechanism and Reactivity After Inflammatory Stimulus

The imbalance between the overproduction of reactive species and antioxidant mechanisms can result in astrogliosis and oxidative stress associated with neurodegeneration. Based on the described antioxidant activity of naturally occurring flavonoids, this study evaluated the antioxidant mechanisms of the flavonoid naringenin and the senecioic acid ester derivatives in cortical astrocytes. Naringenin and (<i>S</i>)-naringenin were purified from <i>Citrus paradisi</i>, and from them 7,4-<i>O</i>-disenecioic ester naringenin, (<i>S</i>)-7,4-<i>O</i>-disenecioic ester naringenin, and 7-<i>O</i>-senecioic ester naringenin were synthesized and tested for antioxidant activity by the free-radical scavenging reaction with DPPH. The flavonoids' toxicity and glutathione (GS) depletion were determined in rat astrocyte cultures; the effects on the astrocytes' reactivity was determined by the expression of the glial fibrillary acidic protein (GFAP) and by measuring nitric oxide (NO) production in astrocytes treated with lipopolysaccharide (LPS, 1 µg/mL/24 h). The compounds (1-10 μM) presented antioxidant effects, and the (<i>S</i>)-7,4'-<i>O</i>-disenecioic ester naringenin was the most effective. The compounds (1-100 μM) were not toxic to the astrocytes, also promoting an antioxidant effect by increasing GSH. Moreover, naringenin, (<i>S</i>)-7,4'-<i>O</i>-disenecioic ester naringenin, and 7-<i>O</i>-senecioc ester naringenin mitigated the astrocyte reactivity induced by LPS, reducing GFAP expression and NO production. These findings indicate that naringenin and senecioic acid ester derivatives present a pharmacological potential as antioxidant and anti-inflammatory compounds for brain diseases via the modulation of astrocyte response.