Mitochondria Superoxide Anion Production Contributes to Geranylgeraniol-Induced Death inLeishmania amazonensis

Abstract

Here we demonstrate the activity of geranylgeraniol, the major bioactive constituent from seeds ofBixa orellana, againstLeishmania amazonensis. Geranylgeraniol was identified through1H and13C nuclear magnetic resonance imaging and DEPT. The compound inhibited the promastigote and intracellular amastigote forms, with IC50of11±1.0and17.5±0.7 μg/mL, respectively. This compound was also more toxic to parasites than to macrophages and did not cause lysis in human blood cells. Morphological and ultrastructural changes induced by geranylgeraniol were observed in the protozoan by electronic microscopy and included mainly mitochondria alterations and an abnormal chromatin condensation in the nucleus. These alterations were confirmed by Rh 123 and TUNEL assays. Additionally, geranylgeraniol induces an increase in superoxide anion production. Collectively, ourin vitrostudies indicate geranylgeraniol as a selective antileishmanial that appears to be mediated by apoptosis-like cell death.