Zebrafish toxicological screening could aid Leishmaniosis drug discovery
| Autor: | Tatiana Corrêa, Hirla Costa Silva Fukushima, Luis Kluwe de Aguiar, Ricardo Lacava Bailone, Princia Grejo Setti, Ricardo Carneiro Borra, Helena Janke |
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| Rok vydání: | 2021 |
| Předmět: |
Medicine (General)
QH301-705.5 Pharmacology Toxicology 3Rs R5-920 In vivo medicine Leishmaniose Biology (General) Zebrafish Cardiotoxicity biology Animal health business.industry Research Neurotoxicity Human health Immunity medicine.disease biology.organism_classification Acute toxicity Drug development Benznidazole Toxicity business medicine.drug |
| Zdroj: | Laboratory Animal Research Laboratory Animal Research, Vol 37, Iss 1, Pp 1-11 (2021) |
| ISSN: | 1738-6055 |
| Popis: | Background Recently a screen from a library of 1.8 million compounds identified in vitro a potent activity of the 2-aminobenzimidazoles series against Leishmania infantum, the etiological agent responsible by over 20.000 deaths each year. Several analogs were synthesized and in vitro tested through an optimization program, leading to a promising 2-aminobenzimidazoles derived compound (2amnbzl-d) that was progressed to in vivo mice studies. However, the not expected toxic effects prevented its progression to more advanced preclinical and clinical phases of drug development. Due to limitations of cell models in detecting whole organism complex interactions, 90% of the compounds submitted to pre-clinical tests are reproved. The use of Zebrafish embryo models could improve this rate, saving mammals, time and costs in the development of new drugs. To test this hypothesis, we compared 2amnbzl-d with two compounds with already established safety profile: carbamazepine and benznidazole, using an embryo Zebrafish platform based on acute toxicity, hepatotoxicity, neurotoxicity and cardiotoxicity assays (Pltf-AcHpNrCd). Results Tests were performed blindly, and the results demonstrated the presence of lethal and teratogenic effects (CL50%: 14.8 µM; EC50%: 8.6 µM), hepatotoxic in concentrations above 7.5 µM and neurotoxic in embryos exposed to 15 µM of 2amnbzl-d. Nevertheless, benznidazole exposition showed no toxicity and only the 100 µM of carbamazepine induced a bradycardia. Conclusions Results using Pltf-AcHpNrCd with zebrafish reproduced that found in the toxicological tests with mammals to a portion of the costs and time of experimentation. |
| Databáze: | OpenAIRE |
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