Zebrafish toxicological screening could aid Leishmaniosis drug discovery
10.1186/s42826-021-00104-1
- Author:
Hirla Costa Silva FUKUSHIMA
1
;
Ricardo Lacava BAILONE
;
Tatiana CORRÊA
;
Helena JANKE
;
Luís Kluwe De AGUIAR
;
Princia Grejo SETTI
;
Ricardo Carneiro BORRA
Author Information
1. Center of Biological and Health Sciences, Federal University of Sao Carlos, Washington Luis Road km 235, Sao Carlos 13565-905, Brazil
- Publication Type:Research
- From:Laboratory Animal Research
2021;37(3):241-251
- CountryRepublic of Korea
- Language:English
-
Abstract:
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.
