Abstract
Artesunate is a semi-synthetic derivative of artemisinin used to treat malaria, and has been shown to possess anti-inflammatory activity. In this study, we have investigated the effect of artesunate on PGE2 production/COX-2 protein expression in LPS+IFNγ-activated BV2 microglia. To further understand the mechanism of action of this compound, we investigated its interference with NF-κB and p38 MAPK signalling pathways. PGE2 production was determined using EIA, while protein expressions of inflammatory targets like COX-2, mPGES-1, IκB, p38 and MAPKAPK2 were evaluated using western blot. An NF-κB-bearing luciferase reporter gene assay was used to test the effect of artesunate on NF-κB-mediated pro-inflammatory gene expression in HEK293 cells stimulated with TNFα (1ng/ml). Artesunate (2 and 4μM), significantly (p <0.01) suppressed PGE2 production in LPS+IFNγ-activated BV2 microglia. This effect was found to be mediated via reduction in COX-2 and mPGES-1 proteins. Artesunate also produced significant inhibition of TNFα and IL-6 production in activated BV2 microglia. Further investigations showed that artesunate (0.5-4μM) significantly (p <0.001) reduced NF-κB-driven luciferase expression, and inhibited IκB phosphorylation and degradation, through inhibition of IKK. Artesunate inhibited phosphorylation of p38 MAPK and its substrate MAPKAPK2 following stimulation of microglia with LPS+IFNγ. Taken together, we have shown that artesunate prevents neuroinflammation in BV2 microglia by interfering with NF-κB and p38 MAPK signalling.
| Original language | English |
|---|---|
| Pages (from-to) | 4726-34 |
| Number of pages | 9 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 22 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - 1 Sep 2014 |
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A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia. / Okorji, Uchechukwu P; Olajide, Olumayokun A.
In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 17, 01.09.2014, p. 4726-34.Research output: Contribution to journal › Article
TY - JOUR
T1 - A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia
AU - Okorji, Uchechukwu P
AU - Olajide, Olumayokun A
N1 - Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - Artesunate is a semi-synthetic derivative of artemisinin used to treat malaria, and has been shown to possess anti-inflammatory activity. In this study, we have investigated the effect of artesunate on PGE2 production/COX-2 protein expression in LPS+IFNγ-activated BV2 microglia. To further understand the mechanism of action of this compound, we investigated its interference with NF-κB and p38 MAPK signalling pathways. PGE2 production was determined using EIA, while protein expressions of inflammatory targets like COX-2, mPGES-1, IκB, p38 and MAPKAPK2 were evaluated using western blot. An NF-κB-bearing luciferase reporter gene assay was used to test the effect of artesunate on NF-κB-mediated pro-inflammatory gene expression in HEK293 cells stimulated with TNFα (1ng/ml). Artesunate (2 and 4μM), significantly (p <0.01) suppressed PGE2 production in LPS+IFNγ-activated BV2 microglia. This effect was found to be mediated via reduction in COX-2 and mPGES-1 proteins. Artesunate also produced significant inhibition of TNFα and IL-6 production in activated BV2 microglia. Further investigations showed that artesunate (0.5-4μM) significantly (p <0.001) reduced NF-κB-driven luciferase expression, and inhibited IκB phosphorylation and degradation, through inhibition of IKK. Artesunate inhibited phosphorylation of p38 MAPK and its substrate MAPKAPK2 following stimulation of microglia with LPS+IFNγ. Taken together, we have shown that artesunate prevents neuroinflammation in BV2 microglia by interfering with NF-κB and p38 MAPK signalling.
AB - Artesunate is a semi-synthetic derivative of artemisinin used to treat malaria, and has been shown to possess anti-inflammatory activity. In this study, we have investigated the effect of artesunate on PGE2 production/COX-2 protein expression in LPS+IFNγ-activated BV2 microglia. To further understand the mechanism of action of this compound, we investigated its interference with NF-κB and p38 MAPK signalling pathways. PGE2 production was determined using EIA, while protein expressions of inflammatory targets like COX-2, mPGES-1, IκB, p38 and MAPKAPK2 were evaluated using western blot. An NF-κB-bearing luciferase reporter gene assay was used to test the effect of artesunate on NF-κB-mediated pro-inflammatory gene expression in HEK293 cells stimulated with TNFα (1ng/ml). Artesunate (2 and 4μM), significantly (p <0.01) suppressed PGE2 production in LPS+IFNγ-activated BV2 microglia. This effect was found to be mediated via reduction in COX-2 and mPGES-1 proteins. Artesunate also produced significant inhibition of TNFα and IL-6 production in activated BV2 microglia. Further investigations showed that artesunate (0.5-4μM) significantly (p <0.001) reduced NF-κB-driven luciferase expression, and inhibited IκB phosphorylation and degradation, through inhibition of IKK. Artesunate inhibited phosphorylation of p38 MAPK and its substrate MAPKAPK2 following stimulation of microglia with LPS+IFNγ. Taken together, we have shown that artesunate prevents neuroinflammation in BV2 microglia by interfering with NF-κB and p38 MAPK signalling.
KW - Animals
KW - Artemisinins
KW - Cell Survival
KW - Cells, Cultured
KW - Dinoprostone
KW - Dose-Response Relationship, Drug
KW - HEK293 Cells
KW - Humans
KW - Interferon-gamma
KW - Lipopolysaccharides
KW - Mice
KW - Microglia
KW - Molecular Structure
KW - NF-kappa B
KW - Structure-Activity Relationship
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.bmc.2014.07.007
DO - 10.1016/j.bmc.2014.07.007
M3 - Article
VL - 22
SP - 4726
EP - 4734
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 17
ER -