Abstract
Cryptococcus neoformans infections rose sharply due to rapid increase in the numbers of immunocompromised individuals in recent years. Treatment of Cryptococcosis in immunocompromised persons is largely very challenging and hopeless. Hence, this study aimed to determine the activity of ellagic acid (EA) in the treatment of C. neoformans in cyclophosphamide injected leukopenic mice. A liposomal formulation of ellagic acid (Lip-EA) was prepared and characterized, and its antifungal activity was assessed in comparison to fluconazole (FLZ). The efficacy of the drug treatment was tested by assessing survival rate, fungal burden, and histological analysis in lung tissues. The safety of the drug formulations was tested by investigating hepatic, renal function, and antioxidant levels. The results of the present work demonstrated that Lip-EA, not FLZ, effectively eliminated C. neoformans infection in the leukopenic mice. Mice treated with Lip-EA (40 mg/kg) showed 70% survival rate and highly reduced fungal burden in their lung tissues, whereas the mice treated with FLZ (40 mg/kg) had 20% survival rate and greater fungal load in their lungs. Noteworthy, Lip-EA treatment alleviated cyclophosphamide-induced toxicity and restored hepatic and renal function parameters. Moreover, Lip-EA treatment restored the levels of superoxide dismutase and reduced glutathione and catalase in the lung tissues. The effect of FLZ or EA or Lip-EA against C. neoformans infection was assessed by the histological analysis of lung tissues. Lip-EA effectively reduced influx of inflammatory cells, thickening of alveolar walls, congestion, and hemorrhage. The findings of the present study suggest that Lip-EA may prove to be a promising therapeutic formulation against C. neoformans in immunocompromised persons.
Highlights
Immunocompromised persons, including AIDS patients, cancer patients, and persons undergoing organ transplantation are easy targets for opportunistic fungal pathogens [1].A majority of fungal infections occur in immunosuppressed persons, but C. neoformans can cause infection in immunocompetent and immunocompromised individuals as well [2]
ellagic acid (EA) exhibited a significant activity against C. neoformans, as shown by the minimum inhibitory concentration (MIC) results
The antifungal effect of FLZ or EA against C. neoformans was measured by the confocal microscopy
Summary
A majority of fungal infections occur in immunosuppressed persons, but C. neoformans can cause infection in immunocompetent and immunocompromised individuals as well [2]. Pharmaceutics 2021, 13, 882 infection of the brain causes more than 60% mortality rate in the infected persons [4]. C. neoformans through the generation of reactive oxygen species and reactive nitrogen species [5,6,7]. Various antifungal agents such as amphotericin B, itraconazole, fluconazole, and flucytosine can be used in the treatment of C. neoformans infection. Amphotericin B is considered a “gold standard” drug to treat fungal infectious diseases. It exerts serious renal and hepatic toxicity in the treated subjects [8]
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