Artemisinin Artesunate Research Articles

191-LB: Artesunate Treatment Improves Hyperglycemia in a Rodent Model of Gestational Glucose Intolerance without Increasing Beta-Cell Mass

Gestational diabetes (GDM) has been associated with a failure to adequately increase maternal β-cell mass (BCM) during pregnancy. The anti-malarial drugs, artemisinins, have been shown to improve glucose homeostasis in rodent models of diabetes by increasing BCM. Our objective was to reverse BCM deficiency and impaired glucose tolerance in a mouse model of GDM using the artemisinin artesunate. In order to produce glucose intolerance in pregnancy, female mice (F0) were fed a low protein (8%, LP) diet during gestation and lactation, and offspring weaned onto control (20%, C) diet. At 6-10 weeks age female offspring (F1) were time-mated and given C diet throughout pregnancy. Artesunate was administered via drinking water from gestational day (GD) 0.5-6.5. We previously found glucose intolerance, mimicking aspects of GDM, in LP-exposed offspring at GD18 when compared to animals fed a C diet. Thus, glucose tolerance tests (GTT) were performed at GD18 or for non-pregnant age-matched animals. Subsequently, pancreata were removed for fluorescence immunohistochemistry to assess histology. Artesunate-treated LP females had a lower area under the curve during a GTT (389.9±52.3mmol/L*min) compared to non-treated LP females at GD18 (726.6±56.9mmol/L*min, p<0.01). Furthermore, artesunate-treated LP females had improved glucose homeostasis at 5min (9.1 vs. 18.9mmol/L), 15min (11.6 vs. 20.9mmol/L) and 30min (10.2 vs. 19.2mmol/L) during the GTT compared to non-treated LP females at GD18 (p<0.05). There were no significant differences in BCM, alpha-cell mass, or mean islet size between LP and artesunate-treated LP females at GD18. The results show that artesunate-treated LP pregnant females had significantly improved glucose homeostasis compared to untreated LP mice at GD18. However, the improved glucose tolerance was not associated with increased BCM or changes in endocrine pancreas morphology. Disclosure S. Szlapinski: None. D.J. Hill: None. Funding St. Joseph's Health Care Foundation; Ontario Graduate Scholarship

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria.