Role of PI3K pathway in the anti-inflammatory effect of Benznidazole

MASCOLO P.; ÁGATA CAROLINA CEVEY; PIERALISI, AZUL V.; SEQUEYRA ALDANA; FEDERICO N PENAS; GERARDO ARIEL MIRKIN; GOREN, NORA

Ciudad autónoma de Buenos Aires

Congreso; XX Simposio Internacional sobre Enfermedades Desatendidas; 2021

Mundo Sano

Benznidazole (Bz) is the drug of choice in many countries for the treatment of Chagas Disease. Although it has been used in clinical settings for a long time, its mechanisms of action have not been fully elucidated yet. Indeed, there is a general premise that the etiological treatment contributes to a reduction of the parasite load and to fit the host immune response, leading to a balanced inflammatory response whichis crucial to control Chagas disease morbidity. In addition to its parasiticidal effect, we have previously reported that Bz inhibits the activation of the NF-kB pathway by increasing the expression of SOCS3 through the IL-10/STAT3/SOCS3 pathway. Furthermore, in preliminary results we showed that PI3K would participate in this effect in cardiac cells. In this work, we assessed this issue in a macrophage (M) cellline (RAW 264.7). The M were pre-treated with 15uM Bz and stimulated with 10 ug/ml of LPS. The treatments were performed, in parallel, in the presence of LY294002, a specific inhibitor of PI3K activity. To deepen the knowledge of themechanism of action, we also used CAL-101, a specific inhibitor of the p110 catalytic subunit of isoform Class IA of PI3K. Inhibition was confirmed with the absence of phosphorilationof P70S6K. In these conditions, we found that Bz couldn?t inhibit the activation of NF-κB, evidenced by the expression ofIκB, the expression of IL-6 and TNFalpha mRNA and the release of nitrites to the culture supernatant. Furthermore, in both inhibition conditions, Bz couldn?t increase SOCS3 expression.These preliminary results suggest that Bz exerts its antiinflammatory effect, not only in an IL-10/STAT3/SOCS3 but also in a Class IA-PI3K dependent manner