RT Journal Article
T1 A short-term treatment with BKI-1294 does not protect foetuses from sheep experimentally infected with Neospora caninum tachyzoites during pregnancy
A1 Sánchez Sánchez, Roberto
A1 Ferré Pérez, Ignacio
A1 Re, Michela Tatiana
A1 Pérez Arroyo, Bárbara
A1 Cleofé Resta, Darío
A1 Herrero García, Victor
A1 Pizarro Díaz, Manuel
A1 Ferrer, Luis Miguel
A1 Ruiz, Hector
A1 Vallejo García, Raquel
A1 Benavides, Julio
A1 Hulverson, Matthew A.
A1 Choi, Ryan
A1 Whitman, Grant R.
A1 Hemphill, Andrew
A1 Van Voorhis, Wesley C.
A1 Ortega Mora, Luis Miguel
AB The Neospora caninum Calcium-dependent protein kinase 1 (NcCDPK1) inhibitor BKI-1294 had demonstrated excellent efficacy in a pregnant mouse model of neosporosis, and was also highly efficacious in a pregnant sheep model of toxoplasmosis. In this work, we present the efficacy of BKI-1294 treatment (dosed 5 times orally every 48 h) starting 48 h after intravenous infection of sheep with 105 Nc-Spain7 tachyzoites at mid-pregnancy. In the dams, BKI-1294 plasma concentrations were above the IC50 for N. caninum for 12–15 days. In treated sheep, when they were compared to untreated ones, we observed a minor increase in rectal temperature, higher IFNγ levels after blood stimulation in vitro, and a minor increase of IgG levels against N. caninum soluble antigens through day 28 post-infection. Additionally, the anti-NcSAG1 and anti-NcSAG4 IgGs were lower in treated dams on days 21 and 42 post-infection. However, BKI-1294 did not protect against abortion (87% foetal mortality in both infected groups, treated and untreated) and did not reduce transplacental transmission, parasite load or lesions in placentomes and foetal brain. The lack of foetal protection was likely caused by short systemic exposure in the dams and suboptimal foetal exposure to this parasitostatic drug, which was unable to reduce replication of the likely established N. caninum tachyzoites in the foetus at the moment of treatment. New BKIs with a very low plasma clearance and good ability to cross the blood-brain and placental barriers need to be developed.
PB Elsevier
SN 2211-3207
YR 2021
FD 2021-10-08
LK https://hdl.handle.net/20.500.14352/4643
UL https://hdl.handle.net/20.500.14352/4643
LA eng
NO CRUE-CSIC (Acuerdos Transformativos 2021)
NO Comunidad de Madrid
NO Swiss National Science Foundation
NO National Institutes of Health, Bethesda
NO United States Department of Agriculture, National Institute of Food and Agriculture
DS Docta Complutense
RD 1 sept 2024