AMPK/Nrf2 signaling is involved in the anti-neuroinflammatory action of Petatewalide B from Petasites japonicus against lipopolysaccharides in microglia
Abstract
OBJECTIVES: Abnormal microglia secrete neuroinflammatory factors that play a pivotal role in neurodegenerative-disorder development. Thus, regulating abnormal microglia-activation could be a promising therapeutic strategy. The purposes of this study included investigating the effect of Petatewalide B on lipopolysaccharide- (LPS-) stimulated microglia and exploring the role of the AMPK/Nrf2- (adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2) signaling pathway in the anti-neuroinflammatory function of Petatewalide B. METHODS: We divided the microglia into four groups: a control group, a Petatewalide B-treated group, an LPS-treated group, and an LPS and Petatewalide B-treated group. The four groups of microglia were experimented with, using the NO, ELISA, and promoter assays, and western blotting was conducted to determine LPS-stimulated neuroinflammatory responses. RESULTS: We found that pretreatment with Petatewalide B strongly alleviates interleukin- (IL-) 1β, IL-6, and tumor-necrosis-factor-α (TNF-α) production, and suppresses iNOS and nitric oxide (NO) overexpression in LPS-stimulated microglia. The AMPK/Nrf2-signaling pathway is important for inducing anti-neuroinflammatory responses. Mechanistic studies report that Petatewalide B increases nuclear-Nrf2 translocation, and heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) expression in a dose-dependent manner. Furthermore, Petatewalide B significantly up-regulates HO-1 and NQO1 by specifically improving antioxidant-response-elements-transcription activity. We then investigated whether Nrf2/HO-1/NQO1 contribute to the anti-neuroinflammatory properties of Petatewalide B. Nrf2, HO-1, and NQO1 small-integrating-ribonucleic-acids (siRNAs) significantly blocked Petatewalide B-attenuated iNOS-promoter-activity in LPS-stimulated microglia. Furthermore, Petatewalide B also up-regulated AMPK-phosphorylation in a dose-dependent manner. We next evaluated whether blocking AMPK-phosphorylation using an inhibitor (compound C) would critically affect anti-neuroinflammatory responses. We found that the AMPK-phosphorylation is associated with nuclear-Nrf2 translocation and elevated HO-1 and NQO1 expression levels. Our data also showed that AMPK-inhibitor pretreatment significantly reverses Petatewalide B-attenuated iNOS-promoter-activity in LPS-stimulated microglia. CONCLUSIONS: Our findings provide the possible mechanism of the anti-neuroinflammatory properties of Petatewalide B that result from beneficial responses in the AMPK/Nrf2-signaling pathway.
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A plethora of plant-derived, quinone-related compounds have been demonstrated to limit microglial inflammation by activation of the Nrf2 pathway and subsequent upregulation of ARE-containing genes.
“A plethora of plant-derived, quinone-related compounds have been demonstrated to limit microglial inflammation by activation of the Nrf2 pathway and subsequent upregulation of ARE-containing genes, including tiliroside, petatewalide B, emodin and β-lapachone, to name a few [176,177,178,179].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [177]
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- Authors
- Park, S. Y., Choi, M. H., Li, M., Li, K., Park, G., & Choi, Y.-W.
- Affiliations
- Pusan National University (KR)
- Department of Horticultural Bioscience, Pusan National University, Myrang, Korea;
- Corresponding author
- Park, Geuntae
- Choi, Young-Whan
- Venue
- Immunopharmacology and Immunotoxicology
- Publisher
- Informa UK Limited
- Published
- 2018-02-12
- Volume
- 40
- Issue
- 3
- Pages
- 232-241
- ISSN
- 0892-3973 (ISSN-L)
- 1532-2513
- OpenAlex
- W2792285207
- Cited by
- 24
- References
- 32
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 6 · 2020: 6 · 2019: 4 · 2018: 2
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Immunopharmacology and Immunotoxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation of Korea (NRF)
- Ministry of Education (NRF-)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- Petasites japonicus, neuroinflammation, microglia, lipopolysaccharide, heme oxygenase-1, NQO1, inducible nitric oxide synthase, nitric oxide, inflammatory cytokines, antioxidant response element, AMPK phosphorylation, neurodegenerative diseases, anti-inflammatory natural products
- MeSH terms
- Animals, Anti-Inflammatory Agents, Cell Line, Lipopolysaccharides, Sesquiterpenes, Signal Transduction, Petasites, NF-E2-Related Factor 2, Mice, AMP-Activated Protein Kinases
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