The Modulatory Effects of Citrus Flavonoid Hesperetin on Nrf2 Expression and NF-kB Signaling Pathway in LPS-Activated BV-2 Microglial Cells

Abstract

<b>Abstract ID 16737</b> <b>Poster Board 294</b> Neurodegenerative diseases have become more prevalent as the population ages. Oxidative stress and neuroinflammation have been suggested as critical factors in the progression of these diseases. Chronic neuroinflammation is a crucial part of the immune response against various pathogens in the central nervous system. The chronic production of proinflammatory mediators and activation of microglial cells may lead to the onset of neurodegenerative diseases, such as Alzheimer9s. Studies have shown that flavonoids can reduce neuroinflammation by modulating specific genes of the NF-kB signaling pathway, which is associated with inflammation in the brain. These natural compounds also upregulate Nrf2, which is a critical transcription factor that combats oxidative stress by inducing the transcription of multiple antioxidant genes. The present study evaluated the effect of hesperetin, a flavonoid, on LPS-activated BV-2 microglial cells. The objective was to investigate the hesperetin modulatory effect on inflammation and oxidative stress. The results show the expression of hesperetin-induced catalase (CAT) and superoxide dismutase (SOD) after 48-h treatment, even after the cells were stimulated with LPS. The same effect was obtained in glutathione (GSH), showing that hesperetin induced the expression of glutathione on LPS-activated BV-2 cells. Data from PCR arrays showed that 100 μM of hesperetin modulated numerous genes that regulate oxidative stress and inflammatory processes. Hesperetin down-regulated mRNA expression of proinflammatory genes <i>ERCC6, NOS2</i>, and <i>NCF1</i> and upregulated the expression of <i>HMOX1</i>, a critical antioxidant gene that aids in reducing excessive oxidative stress. RT-PCR also showed that hesperetin upregulated Nrf2 mRNA expression, which is involved in the transcription of several antioxidant genes. In addition, hesperetin modulated the expression of genes associated with NF-kB signaling, including <i>RELA, NF-kB1, NF-kB2, and NF-kBIA</i>. The lack of expression of these genes has been associated with increased neuroinflammation observed in Alzheimer9s disease. The findings obtained in this study indicate that hesperetin may be a potential candidate for neurodegenerative diseases therapy by upregulating Nrf2 expression and subsequent transcription of antioxidant genes and also by reducing neuroinflammation through the modulation of the NF-kB signaling, which could slow the onset and progression of AD. Support/Funding Information: National Institute of Minority Health and Health Disparities of the NIH U54 MD007582