Eugenia Piauhiensis Vellaff. Essential Oil And Gamma-Elemene Its Major Constituent Exhibit Antileishmanial Activity, Promoting Cell Membrane Damage And In Vitro Immunomodulation

Leishmaniasis is considered as one of the most Neglected Tropical Diseases (NTDs) in the world, caused by protozoan parasites of the genus Leishmania. Treatment of leishmaniasis by chemotherapy remains a challenge because of limited efficacy, toxic side effects, and drug resistance. The search for new therapeutic agents from natural sources has been a constant for the treatment of diseases such as leishmaniasis. The objective of this study was to evaluate the biological activity of Eugenia piauhiensis Vellaff. essential oil (EpEO) and its major constituent gamma-elemene on promastigote and amastigote forms of Leishmania (Leishmania) amazonensis, its cytotoxicity, and possible mechanisms of action. EpEO was more active (IC50 6.43 +/- 0.18 mu g/mL) against promastigotes than gamma-elemene [9.82 +/- 0.15 mu g/mL (48.05 +/- 0.73 mu M)] and the reference drug miltefosine [IC50 17.25 +/- 0.26 mu g/mL (42.32 +/- 0.64 mu M)]. EpEO and gamma-elemene exhibited low cytotoxicity against J774.A1 macrophages, with CC50 225.8 +/- 3.57 mu g/mL and 213.21 +/- 3.3 mu g/mL (1043 +/- 16.15 mu M), respectively. Additionally, EpEO and gamma-elemene present direct activity against the parasite, decreasing plasma membrane integrity. EpEO and gamma-elemene also proved to be even more active against intracellular amastigotes of the parasite [IC50 4.59 +/- 0.07 mu g/mL and 8.06 +/- 0.12 mu g/mL (39.44 +/- 0.59 mu M)], respectively), presenting indirect effects through macrophage activity modulation. Anti-amastigote activity was associated with increased TNF-alpha, IL-12, NO, and ROS levels. In conclusion, our results suggest EpEO and gamma-elemene as promising candidates for new drug development against leishmaniasis.