PIOGLITAZONE AS AN ADJUVANT OF AMPHOTERICIN B FOR THE TREATMENT OF CRYPTOCOCCOSIS

Abstract Approximately 180,000 people worldwide die from cryptococcosis yearly, probably due to the ineffectiveness and toxicity of current drugs available to treat the disease. Amphotericin B (AMB) is effective in killing the fungal, but has serious adverse effects linked to the excessive reactive oxygen species production that compromise renal function. Pioglitazone (PIO) is a PPARγ agonist widely repositioned as adjuvant of different drugs that cause toxic effects to the host due to its antioxidant and anti-inflammatory effects. In this study, we evaluated PIO for the treatment of cryptococcosis in combination with AMB. As a first result, PIO reduced serum creatinine and glutamic-oxalacetic transaminase (GOT) levels in mice treated with PIO+AMB. In vitro , PIO was able to control harmful oxidative bursts induced by AMB, without compromise the antifungal effect. In vivo , PIO+AMB increased the survival rate in comparison to AMB alone and improved the morbidity of the animals. PIO+AMB were more efficient than AMB alone in inhibiting fungal transmigration from the lungs to the brain and in killing yeasts that have reached the central nervous system, avoiding the establishment of meningoencephalitis. In a phagocytosis assay, PIO did not influence the engulfment and fungicidal activity of macrophages induced by AMB, but reduced the oxidative burst after the reduction of fungal burden, pointing to the control of the pathogen without leading to excessive stress that can be damaging to the host. In conclusion, PIO+AMB ameliorates cryptococcosis in murine model, indicating that it is a promising therapeutic adjuvant for combating and controlling the fungal infection.