학술논문
Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice.
Document Type
Academic Journal
Author
Anghel N; Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.; Winzer PA; Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.; Imhof D; Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.; Müller J; Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.; Langa X; Department of Developmental Biology and Regeneration, Institute of Anatomy, University of Bern, Baltzerstrasse 2, CH-3000 Bern, Switzerland.; Rieder J; Centre for Fish and Wildlife Health (FIWI), Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland.; Barrett LK; Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109, USA.; Vidadala RSR; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.; Huang W; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Choi R; Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109, USA.; Hulverson MA; Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109, USA.; Whitman GR; Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109, USA.; Arnold SL; Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109, USA.; Van Voorhis WC; Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109, USA.; Ojo KK; Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98109, USA.; Maly DJ; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.; Fan E; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.; Hemphill A; Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland. Electronic address: andrew.hemphill@vetsuisse.unibe.ch.
Source
Publisher: Elsevier Science Publishers Country of Publication: Netherlands NLM ID: 9111860 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7913 (Electronic) Linking ISSN: 09248579 NLM ISO Abbreviation: Int J Antimicrob Agents Subsets: MEDLINE
Subject
Language
English
Abstract
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 were applied by gavage for 5 days. Five BKIs did not affect pregnancy, five BKIs exhibited ~15-35% neonatal mortality and five 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 fertilised eggs to 0.2-50 μM of BKIs and microscopic monitoring of embryo development in a blinded manner for 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows the calculation of an impact score (S i ) indicating at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for nine compounds no clear correlation between S i and pregnancy outcome was observed. However, the three BKIs affecting zebrafish embryos only at high concentrations (≥40 μM) did not impair mouse pregnancy at all, and the three compounds that inhibited zebrafish embryo development already at 0.2 μM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has 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.
(Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
(Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)