Anti-neuroinflammatory effect of 6,8,1′-tri-O-methylaverantin, a metabolite from a marine-derived fungal strain Aspergillus sp., via upregulation of heme oxygenase-1 in lipopolysaccharide-activated microglia

• Published in: Neurochemistry international 2018-02, Vol.113, p.8-22
• Main Authors: Kim, Kwan-Woo, Kim, Hye Jin, Sohn, Jae Hak, Yim, Joung Han, Kim, Youn-Chul, Oh, Hyuncheol
• Format: Article
• Language: English
• Subjects: 6,8,1′-tri-O-methylaverantin; Animals; Anthraquinones - isolation & purification; Anthraquinones - metabolism; Anthraquinones - pharmacology; Anti-Inflammatory Agents - isolation & purification; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Anti-neuroinflammatory effect; Aspergillus - isolation & purification; Aspergillus - metabolism; Aspergillus sp; Cell Line, Transformed; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Dose-Response Relationship, Drug; Heme Oxygenase-1 - biosynthesis; HO-1; Lipopolysaccharides - toxicity; Membrane Proteins - biosynthesis; Mice; Microglia - drug effects; Microglia - metabolism; Nrf2; Rats; Rats, Sprague-Dawley; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2017.11.010

In the course of searching for anti-neuroinflammatory metabolites from marine-derived fungi, three fungal metabolites, 6,8,1′-tri-O-methylaverantin, 6,8-di-O-methylaverufin, and 5-methoxysterigmatocystin were isolated from a marine-derived fungal strain Aspergillus sp. SF-6796. Among these, 6,8,1′-tri-O-methylaverantin induced the expression of heme oxygenase (HO)-1 protein in BV2 microglial cells. The induction of HO-1 protein was mediated by the activation of nuclear transcription factor erythroid-2 related factor 2 (Nrf2), and was regulated by the p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B signaling pathways. Furthermore, 6,8,1′-tri-O-methylaverantin suppressed the overproduction of pro-inflammatory mediators, such as nitric oxide, prostaglandin E2, inducible nitric oxide synthase, and cyclooxygenase-2 in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. These anti-neuroinflammatory effects were mediated through the negative regulation of the nuclear factor kappa B pathway, repressing the phosphorylation and degradation of inhibitor kappa B-α, translocation into the nucleus of p65/p50 heterodimer, and DNA-binding activity of p65 subunit. The anti-neuroinflammatory effect of 6,8,1′-tri-O-methylaverantin was partially blocked by a selective HO-1 inhibitor, suggesting that its anti-neuroinflammatory effect is at least partly mediated by HO-1 induction. In this study, 6,8,1′-tri-O-methylaverantin also induced HO-1 protein expression in primary microglial cells, and this correlated with anti-neuroinflammatory effects observed in LPS-stimulated primary microglial cells. In conclusion, 6,8,1′-tri-O-methylaverantin represents a potential candidate for use in the development of therapeutic agents for the regulation of neuroinflammation in neurodegenerative diseases. [Display omitted] •6,8,1′-tri-O-methylaverantin activated Nrf2/HO-1 signaling in BV2 cells.•The HO-1 induction was mediated by p38 MAPK and PI3K/Akt cascades.•6,8,1′-tri-O-methylaverantin exhibited anti-inflammatory effect in BV2 cells.•Similar effects were observed in primary microglial cells.