N-acetylcysteine reduces amphotericin B deoxycholate nephrotoxicity and improves the outcome of murine cryptococcosis
| Autor: | Elúzia Castro Peres Emídio, Maria Aparecida Resende-Stoianoff, Rodrigo Assuncao Holanda, Camila Bernardo de Brito, Gabriela Freitas Ferreira, Noelly Queiroz Ribeiro, Daniel Assis Santos, Paulo Henrique Fonseca Carmo, Tatiane A. Paixão, Gustavo José Cota de Freitas, Thais Furtado Ferreira Magalhães, Daniele Glória de Souza, Vanessa S. D. Carvalho, Cláudia Emanuela Viana Rocha, Marliete Carvalho Costa |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Antifungal Agents 030106 microbiology Microbial Sensitivity Tests Pharmacology Kidney Nephrotoxicity Acetylcysteine Lipid peroxidation Mice 03 medical and health sciences chemistry.chemical_compound Amphotericin B Amphotericin B deoxycholate parasitic diseases medicine Animals Lung chemistry.chemical_classification Reactive oxygen species urogenital system Macrophages Drug Repositioning technology industry and agriculture Brain Cryptococcosis General Medicine bacterial infections and mycoses medicine.disease Mice Inbred C57BL Cryptococcus Disease Models Animal Drug Combinations 030104 developmental biology Infectious Diseases chemistry Creatinine Toxicity Female Reactive Oxygen Species Deoxycholic Acid medicine.drug |
| Zdroj: | Medical Mycology. 58:835-844 |
| ISSN: | 1460-2709 1369-3786 |
| DOI: | 10.1093/mmy/myz129 |
| Popis: | Cryptococcosis is a life-threatening fungal infection, and its current treatment is toxic and subject to resistance. Drug repurposing represents an interesting approach to find drugs to reduce the toxicity of antifungals. In this study, we evaluated the combination of N-acetylcysteine (NAC) with amphotericin B (AMB) for the treatment of cryptococcosis. We examined the effects of NAC on fungal morphophysiology and on the macrophage fungicidal activity 3 and 24 hours post inoculation. The therapeutic effects of NAC combination with AMB were investigated in a murine model with daily treatments regimens. NAC alone reduced the oxidative burst generated by AMB in yeast cells, but did not inhibit fungal growth. The combination NAC + AMB decreased capsule size, zeta potential, superoxide dismutase activity and lipid peroxidation. In macrophage assays, NAC + AMB did not influence the phagocytosis, but induced fungal killing with different levels of oxidative bursts when compared to AMB alone: there was an increased reactive oxygen species (ROS) after 3 hours and reduced levels after 24 hours. By contrast, ROS remained elevated when AMB was tested alone, demonstrating that NAC reduced AMB oxidative effects without influencing its antifungal activity. Uninfected mice treated with NAC + AMB had lower concentrations of serum creatinine and glutamate-pyruvate transaminase in comparison to AMB. The combination of NAC + AMB was far better than AMB alone in increasing survival and reducing morbidity in murine-induced cryptococcosis, leading to reduced fungal burden in lungs and brain and also lower concentrations of pro-inflammatory cytokines in the lungs. In conclusion, NAC + AMB may represent an alternative adjuvant for the treatment of cryptococcosis. |
| Databáze: | OpenAIRE |
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