Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis

Abstract

The effects of Astiban, Lucanthone, Hycanthone and Niridazole on autophagic activities in the gastrodermis of Schistosoma mansoni were determined in vivo, using different dosage levels and dosage times. With Astiban, high levels of autophagy were observed in the gastrodermis 2 hours after an injection of the drug into the mouse, and this response had declined by 20 hours, marking a recovery by the parasite from the drug. Hycanthone and Lucanthone produced an autophagic response several days after the onset of treatment, and no recovery was observed in the morphology of the gastrodermis after the drug was discontinued. The effects of Niridazole on the gastrodermis were to produce the most dramatic ultrastructural changes after high doses and over several days of treatment. With all the drugs examined, gastrodermal autophagy was characterized by the formation of vacuoles containing cell components, lipid droplets and sometimes hydrolytic enzyme reaction product. The autophagic vacuoles appeared to be formed by the sequestration of cytoplasmic material by the basal membrane infoldings, and the transfer of enzymes into the vacuole from within the limiting membrane. The residues from intracellular digestion appeared to be emptied into the caecal lumen.

Lucanthone Is a Novel Inhibitor of Autophagy That Induces Cathepsin D-mediated Apoptosis

“…1A). A previous report suggested that lucanthone induced autophagy in schistomes, which was characterized by the formation of autophagic vacuoles (35). However, based on its chemical structure, we hypothesized that lucanthone would disrupt lysosomal function and inhibit the final step in autophagic degradation.…”

Autophagy in the Invading Pathogen

“…Several anti-schistomal drugs have been demonstrated to trigger autophagy in the gastrodermis of the trematode parasite Schistoma mansoni. 13 However, it is unclear if autophagy is the cause of cell death and tissue degeneration, or merely an effect. Similarly, anti-microbial peptides have been described which induce cell death in Leishmania donovani, the causative agent of visceral leishmaniasis, apparently via a mechanism involving autophagy.…”

Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni

“…The most active cinnamates were again synthesized without the double bond (28)(29)(30). However, these were inactive.…”

“…Autophagy is inducible in S. mansoni schistosomula upon starvation [25] and large acidophilic compartments [26,27] are detectable using the fluorescent dye monodansylcadaverine, a relatively specific dye for autophagosomes [28]. Exposure of S. mansoni adult worms to astiban, lucanthone, hycanthone, and niridazole generate autophagic activities in the gastrodermis (gut) of S. mansoni and induce autophagic vacuoles [29]. There appear to be no reports on autophagy in schistosomes that is induced by cinnamic acid derivatives or terpenoids.…”