Artemether: A New Therapeutic Strategy in Experimental Rheumatoid Arthritis

Cuzzocrea, Salvatore; Saadat, Farshid; Paola, Rosanna Di; Mirshafiey, Abbas

doi:10.1080/08923970500418786

Cited by 33 publications

(23 citation statements)

References 45 publications

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“…We have shown that artemether reduced the production of nitric oxide, PGE2, TNFα and IL-6 in LPS-activated BV2 microglia. Earlier studies in rats showed that artemether reduced collagen-induced paw oedema and nitric oxide formation [20]. This would be the first attempt at elucidating the possible mechanisms involved in the anti- shown to induce mPGES-1 expression in rat astrocytes and mouse cerebral neuronal cells [24].…”

Section: Activated Microglia Produce Various Pro-inflammatory Mediatomentioning

confidence: 88%

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Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

et al. 2015

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Artemether, a lipid-soluble derivative of artemisinin has been reported to possess anti-inflammatory properties. In this study, we have investigated the molecular mechanisms involved in the inhibition of neuroinflammation by the drug. The effects of artemether on neuroinflammation-mediated HT22 neuronal toxicity were also investigated in a BV2 microglia/HT22 neuron co-culture. To investigate effects on neuroinflammation, we used LPS-stimulated BV2 microglia treated with artemether (5-40µM) for 24 hours. ELISAs and western blotting were used to detect pro-inflammatory cytokines, nitric oxide, PGE2, iNOS, COX-2 and mPGES-1. BACE-1 activity and Aβ levels were measured with ELISA kits. Protein levels of targets in NF-κB and p38 MAPK signalling, as well as HO-1, NQO1 and Nrf2 were also measured with western blot. NF-κB binding to the DNA was investigated using EMSA. MTT, DNA fragmentation and ROS assays in BV2-HT22 neuronal co-culture were used to evaluate the effects of artemether on neuroinflammation-induced neuronal death. The role of Nrf2 in the anti-inflammatory activity of artemether was investigated in BV2 cells transfected with Nrf2 siRNA. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE2/COX-2/mPGES-1, TNFα, and IL-6), Aβ and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF-κB and p38MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug activated Nrf2 activity by increasing nuclear translocation of Nrf2 and its binding to antioxidant response elements in BV2 cells. Transfection of BV2 microglia with Nrf2 siRNA resulted in the loss of both anti-inflammatory and neuroprotective activities of artemether. We conclude that artemether induces Nrf2 expression and suggest that Nrf2 mediates the anti-inflammatory effect of artemether in BV2 microglia. Our results suggest that this drug has a therapeutic potential in neurodegenerative disorders. 3 KeywordsArtemether, neuroinflammation, BV2 microglia, HT22 hippocampal neurons, NF-κB, Nrf2 4 BackgroundIn the central nervous system (CNS), the microglia plays an important role in immune defence and tissue repair [1]. Under normal conditions, these cells provide surveillance whilst maintaining homeostasis in the brain [2]. In response to injury, harmful toxins, infection or inflammation, microglial cells become activated, secreting pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen/nitrogen species and pro-inflammatory cytokines including IL-6 and TNFα [3,4]. These pro-inflammatory mediators are mainly regulated by the transcription factor NF-κB [5]. NF-κB binds to the DNA and its transcriptional activity regulates several genes, which promote neuroinflammation. The p38 mitogenactivated protein kinase (p38 MAPK) signalling pathway also plays an important role in the expression and activity of pro-inflammatory cytokines in microglial cells [6][7][8].Excessive production o...

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Section: Activated Microglia Produce Various Pro-inflammatory Mediatomentioning

confidence: 88%

“…Although currently used in the treatment of malaria, experiments on experimental rheumatoid arthritis have shown that artemether could be offered as a second-line drug treatment of rheumatoid arthritis [20]. In addition, artemether has been shown to have anti-inflammatory effects in a mouse model of colitis [21].…”

Section: Introductionmentioning

confidence: 99%

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

et al. 2015

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“…It was reported that artemisinin inhibited NF-κB-mediated iNOS expression and NO synthesis [30] . Owing to this property, several artemisinin derivatives were found to be effective for treating experimental arthritis and lupus nephritis in animal models, however, their bioactivity is limited [31][32][33][34] . SM905 is a novel artemisinin derivative with promising immunosuppressive activity in vitro and in vivo [26] , and oral administration of SM905 induced suppression of collagen-induced arthritis in mice [27] .…”

Section: Discussionmentioning

confidence: 99%

SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-κB pathways in RAW 264.7 macrophages

et al. 2009

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Aim: To elucidate the anti-inflammatory potentials and underlying mechanisms of SM905, a novel artemisinin derivative, in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells. Methods: Nitric oxide (NO) generation, cytokine production, and the protein expression levels of inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were examined using a Griess assay, an enzyme-linked immunosorbent assay (ELISA) and a Western blotting assay, respectively. The mRNA expression was measured using real-time PCR. The phosphorylation of extracellular signalregulated kinase1/2 (ERK1/2), p38, c-jun N-terminal kinase (JNK), and the degradation of IκBα were assessed by Western blotting analysis. The nuclear translocation of nuclear factor-κB (NF-κB) was observed using confocal microscopy. Results: Pretreatment with SM905 (0, 0.1, 1, and 10 μmol/L) suppressed LPS-induced NO, TNF-α, IL-1β, and IL-6 production, and decreased both protein and mRNA levels of iNOS and COX-2. The mRNA expression of LPS receptor Toll-like receptor 4 (TLR4) and myeloid differentiation protein-2 (MD-2) was not changed, while LPS-induced CD14 expression was slightly reduced after SM905 treatment. SM905 markedly decreased the activation of ERK1/2, p38 and JNK suppressed the degradation of IκBα, but did not modify the expression of interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription 1 (STAT1) or interferon-inducible protein-10 (IP-10). By using confocal microscopy, we further observed that NF-κB was correspondingly inhibited in SM905-treated cells. Conclusion: SM905 inhibited NO and pro-inflammatory cytokine production in LPS-stimulated RAW 264.7 cells and these effects are at least partially mediated through suppression of the MAPK and NF-κB signaling pathways.

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“…Monomeric compounds or TCM herbal prescriptions can be used for the treatment of RA. Compounds that have been reported to have anti-arthritic effects include: Alkaloids, such as tetramethylpyrazine (13), sinomenine (14) and brucine (15); glycosides, including tripterygium polyglycoside (16), total glucosides of peony (17) and madecassoside (18); lactones, such as artesunate (19) and artemether (20); quinines, such as shikonin (21); and various TCM prescriptions, including Sanwushaoxie decoction (22) and Qingluo Tongbi Granula (23).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the effect of phlomisoside F on complete Freund's adjuvant-induced arthritis

Zhang

Dong²,

Dong

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Phlomis younghusbandii Mukerjee (Labiatae) has been reported to be effective in the treatment of rheumatoid arthritis (RA). In the present study, the anti-inflammatory and anti-arthritic effects of phlomisoside F (PF), isolated from P. younghusbandii Mukerjee (Labiatae), were investigated in male Wistar rats subjected to carrageen-induced paw edema and complete Freund's adjuvant (CFA)-induced arthritis. Arthritis scores were evaluated by a 5-point ordinal scale (scores 0-4). Expression levels of TNF-α, IL-1β, IL-6, IL-10, COX-2 and 5-LOX were determined via ELISA and western blot assays. Subsequent to establishing the edema and arthritis models, oral administration of PF (5, 10 and 20 mg/kg) significantly inhibited mean edema rate, compared with the control group in carrageenan-induced paw edema assay. In addition, administration of PF (5, 10 and 20 mg/kg/day) for 28 days markedly exhibited an anti-arthritic activity by offsetting the body weight loss, inhibiting the paw edema, reducing the arthritis scores and the indices of thymus and spleen, inhibiting the expression levels of TNF-α, IL-1β, IL-6, COX-2 and 5-LOX, and increasing the expression of IL-10, when compared with the respective control group in CFA-induced arthritis assay. In conclusion, PF is a valuable anti-arthritic constituent of P. younghusbandii, and the present study results suggest that this herb may be used in the treatment of RA.

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Artemether: A New Therapeutic Strategy in Experimental Rheumatoid Arthritis

Cited by 33 publications

References 45 publications

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-κB pathways in RAW 264.7 macrophages

Investigation of the effect of phlomisoside F on complete Freund's adjuvant-induced arthritis

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