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NQO1 mediates the anti-inflammatory effects of nootkatone in lipopolysaccharide-induced neuroinflammation by modulating the AMPK signaling pathway
- Source :
- Free radical biologymedicine. 164
- Publication Year :
- 2020
-
Abstract
- Neuroinflammation and oxidative stress play key roles in the progression of neurodegenerative diseases. Thus, the use of potent anti-inflammatory/antioxidant agents has been suggested as a promising therapeutic strategy for neurodegenerative diseases. In the present study, we investigated the anti-inflammatory and antioxidant effects of nootkatone (NKT), a sesquiterpenoid compound isolated from grapefruit, in in vitro and in vivo models of neuroinflammation. In lipopolysaccharide (LPS)-stimulated BV2 microglial cells, NKT inhibited the expression of iNOS, COX-2, and pro-inflammatory cytokines, and increased the expression of the anti-inflammatory cytokine, IL-10. In addition, NKT inhibited reactive oxygen species (ROS) production and upregulated the expression of antioxidant enzymes, such as NQO1 and HO-1. Molecular mechanistic studies showed that NKT inhibited Akt, p38 MAPK, and NF-κB activities, while increasing AMPK, PKA/CREB, and Nrf2/ARE signaling in LPS-stimulated BV2 cells. Since NKT dramatically increased NQO1 expression, we investigated the role of this enzyme using pharmacological inhibition or knockdown experiments. Treatment of BV2 cells with the NQO1-specific inhibitor, dicoumarol, or with NQO1 siRNA significantly blocked NKT-mediated inhibition of NO, ROS, TNF-α, IL-1β, and upregulation of IL-10. Furthermore, NQO1 inhibition reversed the effects of NKT on pro- and anti-inflammatory signaling molecules. Intriguingly, we found that the AMPK inhibitor, compound C, mimicked the effects of dicoumarol, suggesting the presence of a crosstalk between NQO1 and AMPK. Finally, we demonstrated that NKT inhibited microglial activation, lipid peroxidation, and the expression of pro-inflammatory markers in the brains of LPS-injected mice, which was also reversed by dicoumarol. These data collectively suggest that NQO1 plays a critical role in mediating the anti-inflammatory and antioxidant effects of NKT in LPS-induced neuroinflammation by modulating AMPK and its downstream signaling pathways.
- Subjects :
- 0301 basic medicine
Lipopolysaccharides
Cell signaling
p38 mitogen-activated protein kinases
medicine.medical_treatment
Anti-Inflammatory Agents
AMP-Activated Protein Kinases
medicine.disease_cause
Biochemistry
03 medical and health sciences
Mice
0302 clinical medicine
Physiology (medical)
medicine
Animals
Protein kinase B
Neuroinflammation
Polycyclic Sesquiterpenes
Chemistry
NF-kappa B
AMPK
Dicoumarol
Cell biology
030104 developmental biology
Cytokine
Microglia
030217 neurology & neurosurgery
Oxidative stress
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 18734596
- Volume :
- 164
- Database :
- OpenAIRE
- Journal :
- Free radical biologymedicine
- Accession number :
- edsair.doi.dedup.....c907c25de363116f7d67f35808132886