Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-κB activation in cultured astrocytes and microglial BV-2 cells

• Published in: Journal of neuroinflammation Vol. 11; no. 1; p. 118
• Main Authors: Song, Suk-Young, Jung, Yu Yeon, Hwang, Chul Ju, Lee, Hee Peom, Sok, Chang Hyun, Kim, Joo Hwan, Lee, Sang Min, Seo, Hyun Ok, Hyun, Byung Kook, Choi, Dong Young, Han, Sang Bae, Ham, Young Wan, Hwang, Bang Yeon, Hong, Jin Tae
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02-07-2014; BioMed Central
• Subjects: Amyloid beta-Peptides - metabolism; Animals; Animals, Newborn; Astrocytes - drug effects; Benzopyrans - pharmacology; Cell Survival - drug effects; Cells, Cultured; Cyclooxygenase 2 - metabolism; Dioxoles - pharmacology; Electrophoretic Mobility Shift Assay; Glial Fibrillary Acidic Protein - metabolism; Lipopolysaccharides - pharmacology; Microglia - drug effects; NF-kappa B - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Peptide Fragments - metabolism; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/1742-2094-11-118

ent-Sauchinone is a polyphenolic compound found in plants belonging to the lignan family. ent-Sauchinone has been shown to modulate the expression of inflammatory factors through the nuclear factor-kappa B (NF-κB) signaling pathway. It is well known that neuroinflammation is associated with amyloidogenesis. Thus, in the present study, we investigated whether ent-Sauchinone could have anti-amyloidogenic effects through the inhibition of NF-κB pathways via its anti-inflammatory property.
To investigate the potential effect of ent-Sauchinone on anti-neuroinflammation and anti-amyloidogenesis in in vitro studies, we used microglial BV-2 cells and cultured astrocytes treated with ent-Sauchinone (1, 5, and 10 μM) for 24 hours. For the detection of anti-neuro-inflammatory responses, reative oxygen species (ROS) and Nitric oxide (NO) generation and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression were measured with assay kits and western blotting. β-secretase and β-secretase activities and β-amyloid levels were determined for measuring the anti-amyloidogenic effects of ent-Sauchinone by enzyme assay kits. NF-κB and STAT3 signals were detected with electromobility shift assay (EMSA) to study the related signaling pathways. The binding of ent-Sauchinone to STAT3 was evaluated by a pull-down assay and by a docking model using Autodock VINA software (Hoover's Inc., Texas, United states).
ent-Sauchinone (1, 5, and 10 μM) effectively decreased lipopolysaccharide (LPS)-(1 μg/ml) induced inflammatory responses through the reduction of ROS and NO generations and iNOS and COX-2 expressions in cultured astrocytes and microglial BV-2 cells. ent-Sauchinone also inhibited LPS-induced amyloidogenesis through the inhibition of β-secretase and β-secretase activity. NF- κB amyloid and STAT3, critical transcriptional factors regulating not only inflammation but also amyloidogenesis, were also inhibited in a concentration dependent manner by ent-Sauchinone by blocking the phosphorylation of I κB and STAT3 in cultured astrocytes and microglial BV-2 cells. The docking model approach showed that ent-Sauchinone binds to STAT3, and the employment of a STAT3 inhibitor and siRNA reversed ent-Sauchinone-induced inhibition NF-κB activation and Aβ generation.
These results indicated that ent-Sauchinone inhibited neuroinflammation and amyloidogenesis through the inhibition of STAT3-mediated NF-κB activity, and thus could be applied in the treatment of neuro-inflammatory diseases, including Alzheimer's disease.