Host cell cAMP-Epac pathway inhibition by hawthorn extract as a potential treatment for Chagas disease

Benznidazole (BNZ) and nifurtimox (NFX), drugs used in the treatment of Chagas disease (CD), are effective in acute and congenital cases. However, due to the high toxicity of both drugs, the long duration of the treatment, the high doses, and the low effectiveness during the chronic phase, new therapies are needed. Recently, there has been an increase in alternative medicine and natural products popularity. Medicinal herbs emerge as a promising alternative for the development of new therapies against CD. The development of new active drugs requires the identification of new molecular targets. Host cell cAMP-Epac pathway plays a key role during Trypanosoma cruzi invasion. We have previously shown that Epac1 is required during the cAMP-mediated invasion of this parasite. Moreover, vitexin, a natural flavone that protects against ischemia-reperfusion damage, acts by inhibiting the expression of Epac and Rap1 proteins. Vitexin can be found in plants of the genus Crataegus spp., traditionally known as hawthorn, that are of great interest considering their highly documented use as cardio-protectors. In this work, using HPLC-HRMS and MS2, we could confirm the presence of vitexin in an extract of C. oxyacantha (CO-EE). Interenstingly, treating cells with CO-EE, similar results for T. cruzi invasion than the ones observed for Epac1 specific inhibitor ESI-09 were observed. In addition, treated cells have a diminished activated Rap1b, suggesting that the extract could act through the cAMP-Epac signalling pathway. Most significantly, when using CO-EE in conjunction with NFX we observed an addition of the negative effects on the invasion, opening the possibility of decreasing the dosage/time currently used and thus alleviating the secondary side effects of available drugs, as well as the per capita treatment cost of CD.