β-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and matrix metalloproteinases in activated microglia
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BACKGROUND: β-Lapachone (β-LAP) is a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia sp.), and it has been used for treatment of rheumatoid arthritis, infection, and cancer. In the present study, we investigated whether β-LAP has anti-inflammatory effects under in vitro and in vivo neuroinflammatory conditions. METHODS: The effects of β-LAP on the expression of inducible nitric oxide synthase (iNOS), cytokines, and matrix metalloproteinases (MMPs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and rat primary microglia by ELISA, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. Microglial activation and the expression levels of proinflammatory molecules were measured in the LPS-injected mouse brain by immunohistochemistry and RT-PCR analysis. The detailed molecular mechanism underlying the anti-inflammatory effects of β-LAP was analyzed by electrophoretic mobility shift assay, reporter gene assay, Western blot, and RT-PCR analysis. RESULTS: β-LAP inhibited the expression of iNOS, proinflammatory cytokines, and MMPs (MMP-3, MMP-8, MMP-9) at mRNA and protein levels in LPS-stimulated microglia. On the other hand, β-LAP upregulated the expressions of anti-inflammatory molecules such as IL-10, heme oxygenase-1 (HO-1), and the tissue inhibitor of metalloproteinase-2 (TIMP-2). The anti-inflammatory effect of β-LAP was confirmed in an LPS-induced systemic inflammation mouse model. Thus, β-LAP inhibited microglial activation and the expressions of iNOS, proinflammatory cytokines, and MMPs in the LPS-injected mouse brain. Further mechanistic studies revealed that β-LAP exerts anti-inflammatory effects by inhibiting MAPKs, PI3K/AKT, and NF-κB/AP-1 signaling pathways in LPS-stimulated microglia. β-LAP also inhibited reactive oxygen species (ROS) production by suppressing the expression and/or phosphorylation of NADPH oxidase subunit proteins, such as p47(phox) and gp91(phox). The anti-oxidant effects of β-LAP appeared to be related with the increase of HO-1 and NQO1 via the Nrf2/anti-oxidant response element (ARE) pathway and/or the PKA pathway. CONCLUSIONS: The strong anti-inflammatory/anti-oxidant effects of β-LAP may provide preventive therapeutic potential for various neuroinflammatory disorders.
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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 [179]
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- Authors
- Lee, E.-J., Ko, H.-M., Jeong, Y.-H., Park, E.-M., & Kim, H.-S.
- Affiliations
- Ewha Womans University (KR)
- Corresponding author
- Kim, Hee-Sun
- Venue
- Journal of Neuroinflammation
- Published
- 2015-07-16
- Volume
- 12
- Issue
- 1
- Pages
- 133-133
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC4502557
- OpenAlex
- W1653152132
- Cited by
- 91
- References
- 52
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 11 · 2020: 17 · 2019: 10 · 2018: 9 · 2017: 10 · 2016: 8 · 2015: 2
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (Grant code:ID0EXQAE471)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- β-lapachone, naphthoquinones, neuroinflammation, microglial activation, lipopolysaccharide, inducible nitric oxide synthase, inflammatory cytokines, matrix metalloproteinases, heme oxygenase-1, Nrf2/ARE pathway, NADPH oxidase, reactive oxygen species, MAPK signaling, PI3K/Akt signaling, anti-inflammatory activity, antioxidant activity, IL-10, TIMP-2
- MeSH terms
- Animals, Anti-Inflammatory Agents, Cell Line, Cells, Cultured, Disease Models, Animal, Encephalitis, Lipopolysaccharides, Naphthoquinones, Nitrites, Signal Transduction, Cytokines, Interleukin-10, Rats, Sprague-Dawley, Reactive Oxygen Species, Microglia, Tissue Inhibitor of Metalloproteinase-2, Matrix Metalloproteinases, Mice, Rats, Heme Oxygenase-1, Nitric Oxide Synthase Type II, In Vitro Techniques
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