Cytotoxicity of Amphotericin B and AmBisome: In Silico and In Vivo Evaluation Employing the Chick Embryo Model

Ahmad Khosravi; Iraj Sharifi; Hadi Tavakkoli; Elaheh Molaakbari; Sina Bahraminegad; Ehsan Salarkia; Fatemeh Seyedi; Alireza Keyhani; Zohreh Salari; Fatemeh Sharifi; Mehdi Bamorovat; Ali Afgar; Shahriar Dabiri

doi:10.3389/fphar.2022.860598

Cytotoxicity of Amphotericin B and AmBisome: In Silico and In Vivo Evaluation Employing the Chick Embryo Model

Front Pharmacol. 2022 Jun 8:13:860598. doi: 10.3389/fphar.2022.860598. eCollection 2022.

Authors

Affiliations

¹ Leishmaniasis Research Center, Kerman University of Medical Sciences, Kerman, Iran.
² Department of Clinical Science, School of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran.
³ Department of Chemistry, Shahid Bahonar University of Kerman, Kerman, Iran.
⁴ Department of Anatomy, School of Medicine, Jiroft University of Medical, Sciences, Jiroft, Iran.
⁵ Obstetrics and Gynecology Center, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
⁶ Research Center of Tropical and Infectious Diseases Kerman University of Medical Sciences, Kerman, Iran.
⁷ Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran.
⁸ Afzalipour School of Medicine and Pathology and Stem Cells Research Center, Kerman University of Medical Sciences, Kerman, Iran.

Abstract

Leishmaniasis has been identified as a significant disease in tropical and subtropical regions of the world, with Iran being one of the disease-endemic areas. Various treatments have been applied for this disease, and amphotericin B (Amp B) is the second line of treatment. Side effects of this drug have been reported in various organs. The present study investigated the effects of different types of Amp B on fetal organs using in silico and in vivo assays (chicken embryos). In vivo analysis was done by checking pathological changes, angiogenesis, and apoptosis alterations on eggs treated by Amp B and AmBisome. In silico approach was employed to predict the affinity of Amp B and AmBisome to the vascular endothelial growth factor A (VEGF-A), its receptor (KDR1), apoptotic-regulator proteins (Bcl-2-associated X protein (Bax), B-cell lymphoma (Bcl-2), and Caspase-8. The ADME-toxicity prediction reveals that AmBisome possesses a superior pharmacological effect to Amp B. The best result of all the dockings in the Molegro Virtual Docker (MVD) was obtained between Bax, Bcl-2, Caspase-8, KDR1, and VEGF-A targets. Due to the lower Egap (HOMO-LUMO) of AmBisome, the chemical reactivity of AmBisome was higher than that of Amp B. In vivo analysis showed that embryos that received Amp B exhibited less vascular density than AmBisome. Amp B alone significantly increased the expression of apoptosis and decreased angiogenesis genes compared to AmBisome. The histopathology analysis of the treated embryos showed a reduction in the blood vessel collapse and an increase in degenerative and apoptotic-necrotic changes in the embryonic tissues. Overall, the results suggest the potential benefits of AmBisome over Amp B, which might be a better treatment strategy to treat leishmaniasis during pregnancy.

Keywords: amphotericin B; angiogenesis; apoptosis; chick embryo; in silico; in vivo; leishmaniasis; toxicity.