title: Repurposing of antiparasitic drugs: the hydroxy-naphthoquinone buparvaquone inhibits vertical transmission in the pregnant neosporosis mouse model.
abstract: The three anti-malarial drugs artemiside, artemisone, and mefloquine, and the naphthoquinone buparvaquone known to be active against theileriosis in cattle and Leishmania infections in rodents, were assessed for activity against Neospora caninum infection. All four compounds inhibited the proliferation of N. caninum tachyzoites in vitro with IC50 in the sub-micromolar range, but artemisone and buparvaquone were most effective (IC50 = 3 and 4.9 nM, respectively). However, in a neosporosis mouse model for cerebral infection comprising Balb/c mice experimentally infected with the virulent isolate Nc-Spain7, the three anti-malarial compounds failed to exhibit any activity, since treatment did not reduce the parasite burden in brains and lungs compared to untreated controls. Thus, these compounds were not further evaluated in pregnant mice. On the other hand, buparvaquone, shown earlier to be effective in reducing the parasite load in the lungs in an acute neosporosis disease model, was further assessed in the pregnant mouse model. Buparvaquone efficiently inhibited vertical transmission in Balb/c mice experimentally infected at day 7 of pregnancy, reduced clinical signs in the pups, but had no effect on cerebral infection in the dams. This demonstrates proof-of-concept that drug repurposing may lead to the discovery of an effective compound against neosporosis that can protect offspring from vertical transmission and disease.
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, 3012, Bern, Switzerland. joachim.mueller@vetsuisse.unibe.ch.
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, 3012, Bern, Switzerland. adriana.aguado@vetsuisse.unibe.ch.
authors.forename: Adriana
authors.initials: A
authors.lastname: Aguado-Martínez
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, 3012, Bern, Switzerland. alohavera_@hotmail.com.
authors.forename: Vera
authors.initials: V
authors.lastname: Manser
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences G2, North-West University Potchefstroom Campus, 11 Hoffman Street, Potchefstroom, 2531, South Africa. 25904442@nwu.ac.za.
authors.forename: Ho Ning
authors.initials: HN
authors.lastname: Wong
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences G2, North-West University Potchefstroom Campus, 11 Hoffman Street, Potchefstroom, 2531, South Africa. Richard.Haynes@nwu.ac.za.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Haynes
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, 3012, Bern, Switzerland. andrew.hemphill@vetsuisse.unibe.ch.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D003048:Coccidiosis / Q000469:parasitology / Q000517:prevention & control / Q000635:transmission / Q000662:veterinary*; D005260:Female; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control / Q000662:veterinary*; D008297:Male; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000494:pharmacology*; D018688:Neospora / Q000187:drug effects*; D011247:Pregnancy
chemical_list: D000977:Antiparasitic Agents; D009285:Naphthoquinones; C046326:buparvaquone