Neurodegenerative disorders affect more than fifty million Americans each year and represent serious health threats as the population ages. Neuroinflammation and oxidative stress are critical in the onset, progression, and pathogenesis of neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD), and amyotrophic lateral sclerosis (ALS). A wide range of natural compounds has been investigated because of their antioxidant, anti-inflammatory, and neuroprotective properties. The citrus flavonoid hesperetin (HPT), an aglycone of hesperidin found in oranges, mandarins, and lemons, has been extensively reported to exert neuroprotective effects in experimental models of neurogenerative diseases. This review has compiled multiple studies on HPT in both in vivo and in vitro models to study neurodegeneration. We focused on the modulatory effects of hesperetin on the release of cellular anti-inflammatory and antioxidative stress mediators. Additionally, this review discusses the hesperetin effect in maintaining the levels of microRNA (miRNA) and modulating autophagy as it relates to hesperetin’s protective mechanisms against neurodegeneration. Moreover, this review is focused on providing experimental data for hesperetin’s potential as a neuroprotective compound and discusses reported evidence that HPT crosses the blood–brain barrier. In summary, this review shows the evidence available in the literature to indicate the efficacy of hesperetin in delaying the onset of neurodegenerative diseases.

Chronic oxidative stress (OS) and inflammation are implicated in developing and progressing neurodegenerative diseases (NDs). The chronic activation of microglia cells leads to the overproduction of several substances, including nitric oxide and reactive oxygen species, which can induce neurodegeneration. Natural compounds have recently been investigated for their potential to protect cells from OS and to improve many disease-related conditions. Cardamonin (CD) is a bioactive compound in many plants, such as Alpinia katsumadai and Alpinia conchigera. The present study examined the effects of CD on LPS-activated BV-2 microglial cells. The cell viability results showed that the increasing concentrations of CD, ranging from 0.78 to 200 µM, induced BV-2 cell cytotoxicity in a dose–response manner. In the nitric oxide assay, CD concentrations of 6.25 to 25 µM reduced the release of nitric oxide in LPS-activated BV-2 cells by 90% compared to those treated with LPS only (p ≤ 0.0001). CD (6.25 µM) significantly decreased the cellular production of SOD (3-fold (p ≤ 0.05)) and increased the levels of expression of CAT (2.5-fold (p ≤ 0.05)) and GSH (2-fold (p ≤ 0.05)) in the LPS-activated BV-2 cells. Furthermore, on RT-PCR arrays, CD (6.25 µM) downregulated mRNA expression of CCL5/RANTES (5-fold), NOS2 (2-fold), SLC38A1 (3-fold), TXNIP (2-fold), SOD1 (2-fold), SOD2 (1.5-fold) and upregulated GSS (1.9-fold), GCLC (1.7-fold) and catalase (2.9-fold) expression, indicating CD efficacy in modulating genes involved in OS and inflammation. Furthermore, CD (6.25 µM) increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and lowered the levels of Kelch-like ECH-associated protein 1 (Keap1), indicating that this may be the signaling responsible for the elevation of antioxidant factors. Lastly, the results showed that CD (6.25 µM) modulated genes and proteins associated with the NF-kB signaling, downregulating genes related to excessive neuroinflammation. These results imply that CD may be a potential compound for developing therapeutic and preventive agents in treating neurodegeneration induced by excessive OS and inflammation.

ID 16737 Poster Board 294Neurodegenerative 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 Alzheimer's. 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 mM of hesperetin modulated numerous genes that regulate oxidative stress and inflammatory processes. Hesperetin down-regulated mRNA expression of proinflammatory genes ERCC6, NOS2, and NCF1 and upregulated the expression of HMOX1, 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 RELA, NF-kB1, NF-kB2, and NF-kBIA. The lack of expression of these genes has been associated with increased neuroinflammation observed in Alzheimer's 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.