The Antimalarial Artemisinin Synergizes with Antibiotics To Protect against Lethal Live Escherichia coli Challenge by Decreasing Proinflammatory Cytokine Release

Department of Pharmacology, College of Medicine, The Third Military Medical University, Gaotanyan Street 30, Shapingba District, Chongqing 400038, People's Republic of China.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 08/2006; 50(7):2420-7. DOI: 10.1128/AAC.01066-05
Source: PubMed


In the present study artemisinin (ART) was found to have potent anti-inflammatory effects in animal models of sepsis induced
by CpG-containing oligodeoxy-nucleotides (CpG ODN), lipopolysaccharide (LPS), heat-killed Escherichia coli 35218 or live E. coli. Furthermore, we found that ART protected mice from a lethal challenge by CpG ODN, LPS, or heat-killed E. coli in a dose-dependent manner and that the protection was related to a reduction in serum tumor necrosis factor alpha (TNF-α).
More significantly, the administration of ART together with ampicillin or unasyn (a complex of ampicillin and sulbactam) decreased
mortality from 100 to 66.7% or 33.3%, respectively, in mice subjected to a lethal live E. coli challenge. Together with the observation that ART alone does not inhibit bacterial growth, this result suggests that ART
protection is achieved as a result of its anti-inflammatory activity rather than an antimicrobial effect. In RAW264.7 cells,
pretreatment with ART potently inhibited TNF-α and interleukin-6 release induced by CpG ODN, LPS, or heat-killed E. coli in a dose- and time-dependent manner. Experiments utilizing affinity sensor technology revealed no direct binding of ART
with CpG ODN or LPS. Flow cytometry further showed that ART did not alter binding of CpG ODN to cell surfaces or the internalization
of CpG ODN. In addition, upregulated levels of TLR9 and TLR4 mRNA were not attenuated by ART treatment. ART treatment did,
however, block the NF-κB activation induced by CpG ODN, LPS, or heat-killed E. coli. These findings provide compelling evidence that ART may be an important potential drug for sepsis treatment.

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    • "Antimalarial drugs have been used in the treatment of other pathologies besides malaria. The administration of artemisinin protects against sepsis in mice challenged with lipopolysaccharide by decreasing the secretion of proinflammatory cytokines [19]. However, a possible renal protection effect of antimalarials during a second kidney insult can be rule out because there is no difference in renal injury observed in the noninfected (control+treated+BSA21d) and kidney insult (control+BSA21d) groups. "
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    ABSTRACT: Malaria is a worldwide disease that leads to 1 million deaths per year. Plasmodium falciparum is the species responsible for the most severe form of malaria leading to different complications. Beyond the development of cerebral malaria, impairment of renal function is a mortality indicator in infected patients. Treatment with antimalarial drugs can increase survival, however the long-term effects of malaria on renal disease, even after treatment with antimalarials, are unknown. The aim of this study was to evaluate the effect of antimalarial drug treatment on renal function in a murine model of severe malaria and then evaluate kidney susceptibility to a second renal insult. Initially, mice infected with Plasmodium berghei ANKA achieved 20% parasitemia on day 5 post infection, which was completely abolished after treatment with 25 mg/kg artesunate and 40 mg/kg mefloquine. The treatment also decreased plasma creatinine levels by 43% and partially reversed the reduction in the glomerular filtration rate induced by infection. The urinary protein/creatinine ratio, collagen deposition, and size of the interstitial space decreased by 75%, 40%, and 20%, respectively, with drugs compared with untreated infected animals. In infected-treated mice that underwent a second renal insult, the plasma creatinine level decreased by 60% and the glomerular filtration rate increased compared with infected animals treated only with antimalarials. The number of glomerular cells, collagen deposition and the size of the interstitial space decreased by 20%, 39.4%, and 41.3%, respectively, in the infected group that underwent a second renal insult compared with the infected-treated groups. These functional and structural data show that renal injury observed in a murine model of severe malaria is partially reversed after antimalarial drug treatment, making the kidney less susceptible to a second renal insult.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "Artesunate and artemisinin derivatives have activities demonstrated in different pathologies, such as microbial infections, tumor growth, and inflammatory diseases [3] [4] [8] [32] [33]. In vitro studies demonstrated that artesunate treatment impaired the proliferation of phytohemagglutininstimulated peripheral blood mononuclear cells [7] and decreased the neutrophil capacity to phagocytose Escherichia coli in vitro [32]. "
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    ABSTRACT: Artemisinin and its derivates are an important class of antimalarial drug and are described to possess immunomodulatory activities. Few studies have addressed the effect of artesunate in the murine malaria model or its effect on host immune response during malaria infection. Herein, we study the effect of artesunate treatment and describe an auxiliary mechanism of artesunate in modulating the inflammatory response during experimental malaria infection in mice. Treatment with artesunate did not reduce significantly the parasitemia within 12 h, however, reduced BBB breakdown and TNF-α mRNA expression in the brain tissue of artesunate-treated mice. Conversely, mefloquine treatment was not able to alter clinical features. Notably, artesunate pretreatment failed to modulate the expression of LFA-1 in splenocytes stimulated with parasitized red blood cells (pRBCs) in vitro; however, it abrogated the expression of ICAM-1 in pRBC-stimulated endothelial cells. Accordingly, a cytoadherence in vitro assay demonstrated that pRBCs did not adhere to artesunate-treated vascular endothelial cells. In addition, NF-κB nuclear translocation in endothelial cells stimulated with pRBCs was impaired by artesunate treatment. Our results suggest that artesunate is able to exert a protective effect against the P. berghei-induced inflammatory response by inhibiting NF-κB nuclear translocation and the subsequent expression of ICAM-1.
    Full-text · Article · Oct 2012
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    • "It established potent anti-inflammatory effects in animal models of sepsis induced by CpG- ODN, LPS, heat-killed E. coli 35218 or live E. coli in RAW2647 cells. This, most likely, was mediated through blockage of the NF-kappaB activation by artemisinin (Wang et al., 2006). In addition, artemisinin (50 mg/kg, intraperitoneal) has depicted strong anti-inflammatory activity in rats suffering from acute pancreatitis (Zhao et al., 2007). "
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    ABSTRACT: Artemisinins in combination with other antimalarial drugs remain the mainstay of current antimalarial armamentarium. It is interesting to note that many traditional drugs with antiprotozoal background can wield immunomodulation on the recipient's immune system in a positive or negative direction. Artemisinins also attribute immunomodulatory distensions. For instance, they demonstrate predominant immunosuppressive traits toward different immune components by particularly regulating the cellular proliferation and cytokine release, which indicates that they possess some additional mechanisms and features demanding deliberate attentions. This article reviews the data-based immunomodulatory effects of artemisinins on different immune cells including neutrophils, macrophages, splenocytes, T and B cells in conjunction with their therapeutic prospective with regard to inflammation, autoimmunity and delayed-type hypersensitivity.
    Full-text · Article · Jul 2011 · European journal of pharmacology
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