Insights into the mode of action of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89) against adult Schistosoma mansoni worms

• Published in: Parasitology international Vol. 67; no. 4; pp. 403 - 412
• Main Authors: Blay, Emmanuel Awusah, Kumagai, Takashi, Yamabe, Masafumi, Hino, Akina, Shimogawara, Rieko, Kim, Hye-Sook, Sato, Akira, Ichimura, Koichiro, Ayi, Irene, Iwanaga, Shiroh, Ohta, Nobuo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2018
• Subjects: 1,2,6,7-Tetraoxaspiro [7.11] nonadecane; Animals; Disease Models, Animal; Heterocyclic Compounds, 2-Ring - administration & dosage; Heterocyclic Compounds, 2-Ring - adverse effects; Heterocyclic Compounds, 2-Ring - therapeutic use; Liver - drug effects; Liver - parasitology; Mice; Novel treatment; Oocytes - drug effects; Parasite Egg Count; Physiological Phenomena - drug effects; Schistosoma mansoni; Schistosoma mansoni - drug effects; Schistosomiasis; Schistosomiasis - drug therapy; Schistosomiasis - parasitology; Schistosomiasis mansoni - drug therapy; Schistosomiasis mansoni - parasitology; Spiro Compounds - administration & dosage; Spiro Compounds - adverse effects; Spiro Compounds - therapeutic use; Schistosomiasis; Schistosoma mansoni; 1,2,6,7-Tetraoxaspiro [7.11] nonadecane; Novel treatment
• ISSN: 1383-5769; 1873-0329
• DOI: 10.1016/j.parint.2018.03.006

Control of morbidity associated with schistosomiasis via chemotherapy largely relies on the drug praziquantel. Repeated therapy with praziquantel has created concerns about the possible selection of resistant worms and necessitated the search for novel drugs to treat schistosomiasis. Here, a murine model was infected with Schistosoma mansoni and treated with oral 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89), which caused a significant reduction in fecundity and egg burden and reduced morbidity when administered at 5-weeks post-infection. The analysis showed that the mode of action occurred through the ingestion of activated N-89 by the worms, and that there was no direct external effect on the S. mansoni worms. Ultrastructural analysis of the treated worms showed disruptions in the gut lumen and the presence of large volumes of material, suggestive of undigested blood meals or red blood cells. In addition, there were reduced vitelline cells in female worms and damage to sub-tegmental musculature in male worms. Eggs recovered from the treated mice showed both damage to the eggs and the production of immature eggs. Expression of mRNA responsible for gut and digestive function and egg production was also significantly affected by N-89 treatment, whereas control genes for musculature showed no significant changes. Thus, N-89 drastically affected the total digestive function and egg production of S. mansoni worms. Physiological processes requiring heme uptake such as egg production and eggshell formation were subsequently affected, suggesting that the compound could be a possible therapeutic drug candidate for schistosomiasis control. [Display omitted] •N-89 drastically affected the total digestive function of S. mansoni worms.•N-89 caused ultrastructural damages to S. mansoni worms and eggs.•N-89 affected egg development and digestion related genes.