Comparative assessment of the effects of bumped kinase inhibitorson early zebrafish embryo development and pregnancy in mice.

Anghel, Nicoleta; Winzer, Pablo A.; Imhof, Dennis; Müller, Joachim; Langa, Javier; Rieder, Jessica; Barrett, Lynn K.; Vidadala, Rama Subba Rao; Huang, Wenlin; Choi, Ryan; Hulverson, Mathew A.; Whitman, Grant R.; Arnold, Samuel L.; Van Voorhis, Wesley C.; Ojo, Kayode K.; Maly, Dustin J.; Fan, Erkang; Hemphill, Andrew (2020). Comparative assessment of the effects of bumped kinase inhibitorson early zebrafish embryo development and pregnancy in mice. International journal of antimicrobial agents, 56(3), p. 106099. Elsevier 10.1016/j.ijantimicag.2020.106099

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Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy against Neospora caninum tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice, were assessed in pregnant mice. Drugs were emulsified in corn oil and applied by gavage for 5 days. Five BKIs did not affect pregnancy, 5 BKIs exhibited 15-35% of neonatal mortality, and 5 compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilized eggs to 0.2-50μM of BKIs and microscopical monitoring of embryo development in a blinded manner during 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows to calculate an impact score (Si) that indicates at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for 9 compounds no clear correlation between Si and pregnancy outcome was visible. However, those 3 BKIs affecting zebrafish embryos only at high concentrations (40μM or higher) did not impair mouse pregnancy at all, and those 3 compounds that inhibited zebrafish embryo development already at 0.2μM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has a limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude, that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Functional Anatomy
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Center for Fish and Wildlife Health (FIWI)

UniBE Contributor:

Anghel, Nicoleta; Winzer, Pablo Arnold; Imhof, Dennis; Müller, Joachim; Langa Oliva, Javier; Rieder, Jessica Marie and Hemphill, Andrew

Subjects:

600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

0924-8579

Publisher:

Elsevier

Language:

English

Submitter:

Jessica Marie Rieder

Date Deposited:

01 Feb 2021 14:20

Last Modified:

07 Feb 2021 02:56

Publisher DOI:

10.1016/j.ijantimicag.2020.106099

PubMed ID:

32707170

BORIS DOI:

10.48350/145325

URI:

https://boris.unibe.ch/id/eprint/145325

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