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The Modulatory effects of Hesperitin on the Expression of Oxidative Stress Associated Genes in LPS‐Activated BV‐2 Microglial Cells

Numerous natural compounds have been reported to protect against oxidative stress and decrease the mortality related to chronic diseases. Flavonoids are known to protect against reactive oxygen species (ROS) damage. Many studies suggested a possible protective role of flavonoids in neurodegenerative and inflammatory conditions associated with excessive oxidative stress in the brain. In this study, we evaluated the effect of hesperetin, a major flavonoid found in oranges and mandarins, on LPS‐activated BV‐2 microglial cells. The methodology included cell viability, ELISA, RT‐PCR using individual primers, and PCR arrays to screen a range of genes associated with oxidative stress. Cell viability results showed that only the highest concentration of 200 µM of hesperitin had a toxic effect on the BV‐2 microglial cells, causing 20% of cell death. The combination of LPS and hesperitin also exhibited no toxicity in concentrations ranging from 0.78 to 100 µM. Still, in the concentration of 200 µM, there was a reduction of 50% of cell viability after 24 h. The ELISA and RT‐PCR data demonstrated that hesperitin increased the expression of PDL‐1 in the protein and transcription level in the LPS‐activated cells. Also, hesperitin induced the mRNA expression of Nrf2, which is involved in the transcription of several antioxidant genes, and up‐regulated the expression of MMP‐9, which participates in the cleavage of extracellular matrix and plays a critical role in the central nervous system function. Also, the data from the oxidative stress PCR arrays showed that after 24 h, of cell treatment with 100 µM of hesperitin modulated numerous genes that regulate the oxidative stress process. The results show that hesperitin down‐regulated the mRNA expression of Nos2, Ptgs2, Ncf1, Actb, Txnip, Ucp2, and up‐regulated expression Srxn1, Prdx3, and Txn1. These genes participate not only in excessive oxidative stress processes by also in exacerbated inflammatory states. These data show that hesperitin may have a potential in the prevention and treatment of oxidative stress‐related neurodegenerative diseases.