Anti-Malarial Drug Artesunate Attenuates Experimental Allergic Asthma via Inhibition of the Phosphoinositide 3-Kinase/Akt Pathway

Abstract

BackgroundPhosphoinositide 3-kinase (PI3K)/Akt pathway is linked to the development of asthma. Anti-malarial drug artesunate is a semi-synthetic derivative of artemisinin, the principal active component of a medicinal plant Artemisia annua, and has been shown to inhibit PI3K/Akt activity. We hypothesized that artesunate may attenuate allergic asthma via inhibition of the PI3K/Akt signaling pathway.Methodology/Principal FindingsFemale BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Artesunate dose-dependently inhibited OVA-induced increases in total and eosinophil counts, IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid. It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, IL-17, IL-33 and Muc5ac in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, artesunate blocked epidermal growth factor-induced phosphorylation of Akt and its downstream substrates tuberin, p70S6 kinase and 4E-binding protein 1, and transactivation of NF-κB. Similarly, artesunate blocked the phosphorylation of Akt and its downstream substrates in lung tissues from OVA-challenged mice. Anti-inflammatory effect of artesunate was further confirmed in a house dust mite mouse asthma model.Conclusion/SignificanceArtesunate ameliorates experimental allergic airway inflammation probably via negative regulation of PI3K/Akt pathway and the downstream NF-κB activity. These findings provide a novel therapeutic value for artesunate in the treatment of allergic asthma.

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…Female BALB/c mice, 6-8 weeks old (Canning Vale, Western Australia, Australia), were sensitized and challenged with ovalbumin (OO) to develop experimental asthma as described (Cheng et al 2011;Ho et al 2012). Artesunate (30 mg/kg) was dissolved in 5 % DMSO, given intraperitoneally (i.p.)…”

“…Mice were anesthetized 24 h after the last aerosol challenge and cardiac puncture and BAL were performed (Cheng et al 2011). Blood was collected 5 min postanaesthesia and incubated at room temperature for 1 h prior centrifugation for serum collection.…”

“…Blood was collected 5 min postanaesthesia and incubated at room temperature for 1 h prior centrifugation for serum collection. Total and differential cell counts were determined from BALF collected as described previously (Cheng et al 2011). BALF and serum supernatants were frozen at -80°C prior further analysis.…”

“…Apart from its effective anti-malarial actions, artesunate has promising anti-inflammatory potential in animal models of rheumatoid arthritis (Mirshafiey et al 2006;Li et al 2013), systemic lupus erythematosus (Jin et al 2009) and bacteria-induced sepsis (Li et al 2010;Jiang et al 2011). Recently, studies have demonstrated broad anti-inflammatory and anti-oxidative properties of artesunate in experimental allergic asthma (Cheng et al 2011;Ho et al 2012). In addition, artesunate could prevent IgE-mediated mast cell degranulation in experimental anaphylaxis models .…”

Biochemical Indices of Cardaic Function of Albino Wistar Rats Exposed to Hippocratea Africana Root Bark Extract

“…However, it has been shown to affect airway smooth muscles, inhibiting the proliferation of human cultured airway smooth muscle cells, causing hyperplasia and hypertrophy leading to obstruction of airways [25]. In a report by Hitti, (2004) [26], administration of high doses of artesunate was shown to have cardio toxic effect.…”