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.
Highlights
Neospora caninum is a cyst-forming apicomplexan parasite closely related to Toxoplasma gondii
In vivo efficacies in a Balb/c mouse model for cerebral N. caninum infection In order to investigate whether artemisone, artemiside and mefloquine affected N. caninum infection, the three anti-malarials were applied in male BALB/c that were infected with 105 N. caninum Nc-Spain7 tachyzoites
In order to investigate whether drug repurposing may be a suitable strategy for obtaining suitable chemotherapeutic agents against neosporosis, we have tested four compounds, namely artemiside, artemisone, mefloquine, and buparvaquone, with proven efficacies against apicomplexan parasites in vitro and in mouse models
Summary
Neospora caninum is a cyst-forming apicomplexan parasite closely related to Toxoplasma gondii. N. caninum is one of the most important infectious causes of bovine abortion, stillbirth, and the birth of weak calves, with an economic impact of over 1.3 billion US dollars [1,2,3]. N. caninum infection can result in birth of clinically healthy, but persistently infected calves transmitting the parasite to the generation. N. caninum causes neuromuscular disease in dogs, and neosporosis has been detected in a wide range of other species of livestock and wild animals worldwide. Possible strategies to limit the economic impact of neosporosis include testing and culling of seropositive animals, discontinued breeding with offspring from seropositive cows, vaccination of susceptible and infected animals, and chemotherapeutical treatment of calves from seropositive cows [4, 5]. The most effective option is not always the most economic one [6] and the suitability of any of these options has to be assessed [6, 7]
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