Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jun 23:11:684525.
doi: 10.3389/fcimb.2021.684525. eCollection 2021.

Efficacy of Ebselen Against Invasive Aspergillosis in a Murine Model

Karina Mayumi Sakita  1 , Isis Regina Grenier Capoci  1 , Pollyanna Cristina Vincenzi Conrado  1 , Franciele Abigail Vilugron Rodrigues-Vendramini  1 , Daniella Renata Faria  1 , Glaucia Sayuri Arita  1 , Tânia Cristina Alexandrino Becker  2 , Patricia de Souza Bonfim-Mendonça  1 , Terezinha Inez Estivalet Svidzinski  1 , Erika Seki Kioshima  1
Affiliations

Efficacy of Ebselen Against Invasive Aspergillosis in a Murine Model

Karina Mayumi Sakita et al. Front Cell Infect Microbiol. .

Abstract

Invasive aspergillosis is one of the major causes of morbidity and mortality among invasive fungal infections. The search for new antifungal drugs becomes imperative when existing drugs are not able to efficiently treat these infections. Ebselen, is an organoselenium compound, already successfully approved in clinical trials as a repositioned drug for the treatment of bipolar disorder and prevention of noise-induced hearing loss. In this study, we aimed to reposition ebselen for the treatment of invasive aspergillosis by showing ebselen effectiveness in a murine model. For this, BALB/c mice were immunosuppressed and infected systemically with Aspergillus fumigatus. Animals were divided and treated with ebselen, voriconazole, or drug-free control, for four days. The kidneys were used for CFU count and, histopathological and cytokine analysis. Ebselen was able to significantly reduce the fungal burden in the kidneys of infected mice with efficacy comparable with voriconazole treatment as both had reductions to the same extent. The absence of hyphae and intact kidney tissue structure observed in the histopathological sections analyzed from treated groups corroborate with the downregulation of IL-6 and TNF. In summary, this study brings for the first time in vivo evidence of ebselen efficacy against invasive aspergillosis. Despite these promising results, more animal studies are warranted to evaluate the potential role of ebselen as an alternative option for the management of invasive aspergillosis in humans.

Keywords: Aspergillus; antifungal; ebselen; murine model; systemic infection.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Fungal burden in the kidney after systemic infection by A. fumigatus (ATCC 64026). Control: mice treated with placebo; ebselen: mice treated with 10 mg.kg–1 (765.8 μmoles per mouse) of ebselen; voriconazole: mice treated with 10 mg.kg–1 (572.5 µmoles per mouse) of voriconazole. All groups were treated intraperitoneally twice daily for 4 days starting 1 day after infection. *p < 0.05. Error bars correspond to the standard deviation.
Figure 2
Figure 2
Histological findings in the kidney of immunocompromised BALB/c mice inoculated with Aspergillus fumigatus after five days of systemic infection. (A) Control: mice treated with placebo; (B) voriconazole: mice treated with 10 mg.kg−1 (572.5 µmoles per mouse); (C) ebselen: mice treated with 10 mg.kg−1 (765.8 µmoles per mouse) of ebselen. The treatments were performed intraperitoneally, twice a day, for four days. Tissues were stained with Grocott–Gomori’s methenamine silver (GMS) and hematoxylin and eosin (H&E); magnification, ×400. Asterisk: coagulative necrosis; arrow’s head: hyphae; arrow: mononuclear cell; star: hemorrhage.
Figure 3
Figure 3
Systemic and local inflammatory cytokine evaluation in mice after treatment with EbSe or voriconazole. (A) Cytokines recovered from serum and (B) kidney homogenates from mice treated with placebo, EbSe, or voriconazole (VOR). *p < 0.05, **p < 0.01, ***p <0.001; ****p <0.0001, significant difference compared with control from each cytokine. TNF, tumor necrosis factor; MCP-1, macrophage/monocyte chemoattractant protein-1; IL-6, interleukin-6. Error bars correspond to the standard deviation.
See this image and copyright information in PMC

References

    1. Øya E., Becher R., Ekeren L., Afanou A. K. J., Øvrevik J., Holme J. A. (2019). Pro-Inflammatory Responses in Human Bronchial Epithelial Cells Induced by Spores and Hyphal Fragments of Common Damp Indoor Molds. Int. J. Environ. Res. Public Health 16 (6), 1085. 10.3390/ijerph16061085 - DOI - PMC - PubMed
    1. Binder J., Shadkchan Y., Osherov N., Krappmann S. (2020). The Essential Thioredoxin Reductase of the Human Pathogenic Mold Aspergillus Fumigatus Is a Promising Antifungal Target. Front. Microbiol 1, 1383. 10.3389/fmicb.2020.01383 - DOI - PMC - PubMed
    1. Capoci I. R. G., Faria D. R., Sakita K. M., Rodrigues-Vendramini F. A. V., Bonfim-Mendonça P. S., Becker T. C. A., et al. . (2019). Repurposing Approach Identifies New Treatment Options for Invasive Fungal Disease. Bioorg. Chem. 84, 87–97. 10.1016/j.bioorg.2018 - DOI - PubMed
    1. Cho S. Y., Lee D. G., Kim W. B., Chun H. S., Park C., Myong J. P., et al. . (2019). Epidemiology and Antifungal Susceptibility Profile of Aspergillus Species: Comparison Between Environmental and Clinical Isolates From Patients With Hematologic Malignancies. J. Clin. Microbiol. 57 (7), e02023–e02018. 10.1128/JCM.02023-18 - DOI - PMC - PubMed
    1. ClinicalTrials.gov (2020). Identifier NCT04484025, Spi-1005 Treatment in Moderate Covid-19 Patients (Bethesda, MD: National Library of Medicine US; ). Available at: https://clinicaltrials.gov/ct2/show/NCT04484025.

Publication types