Effectiveness of the sesquiterpene (-)-α-bisabolol in dogs with naturally acquired canine leishmaniosis: an exploratory clinical trial.

The use of natural products is a promising approach for treating visceral leishmaniosis. (-)-α-Bisabolol is a sesquiterpene that have been proved active in vivo on Leishmania infantum-infected mice without showing toxicity. A single-centre, parallel-group, randomized, exploratory study was designed to assess its efficacy in a canine leishmaniosis model involving naturally infected dogs. In this clinical trial, 12 dogs were allocated into two groups and were treated with either meglumine antimoniate (100 mg/kg) through subcutaneous route or (-)-α-bisabolol (30 mg/kg) through oral route for two treatment series of 30 days, separated by a 30-day interval. A 4-month follow-up period was established as well. Parasite loads in bone marrow, lymph node and blood were estimated through quantitative PCR. Antibody titres were determined through immunofluorescence antibody test and cytokine expression values were estimated through real-time reverse transcription-PCR. Treatment safety was assessed through the evaluation of weight, gastrointestinal alterations and hematological and biochemical parameters in blood. Analyses were performed before and after treatment, and after a 4-months follow-up period. Treatment with the sesquiterpene was effective at decreasing parasite loads and increasing gamma-interferon expression level. Dogs treated with (-)-α-bisabolol did not show any toxicity sign. These results were better than those obtained using the reference drug, meglumine antimoniate. The natural compound seemed to induce a Th1 immune response that led to parasitological and clinical improvement without showing any safety issue, suggesting a high potential for the treatment of canine and human visceral leishmaniosis.

The sesquiterpene (-)-α-bisabolol is active against the causative agents of Old World cutaneous leishmaniasis through the induction of mitochondrial-dependent apoptosis.

Cutaneous leishmaniasis treatment remains challenging due to the absence of a satisfactory treatment. The screening of natural compounds is a valuable strategy in the search of new drugs against leishmaniasis. The sesquiterpene (-)-α-bisabolol is effective in vivo against visceral leishmaniasis due to Leishmania infantum, but its mechanism of action remains elusive. The aim of this study is to validate this promising compound against the causative species of Old World cutaneous leishmaniasis and to get an insight into its antileishmanial mode of action. The compound was evaluated on L. tropica promastigotes and intracellular amastigotes using bone marrow-derived macrophages and its cytotoxicity was evaluated on L929 fibroblasts. The reactive oxygen species generation was evaluated using a sensitive probe. Mitochondrial depolarization was assessed evaluating the fluorescence due to rhodamine 123 in a flow cytometer. Apoptosis was investigated by measuring the fluorescence due to annexin V and propidium iodide in a flow cytometer. The ultrastructure of treated promastigotes and intracellular amastigotes was analysed through transmission electron microscopy. (-)-α-Bisabolol was active against L. tropica intracellular amastigotes displaying an inhibitory concentration 50 % of 25.2 µM and showing low cytotoxicity. This compound induced time and dose-dependent oxidative stress, mitochondrial depolarization and phosphatidilserine externalization (a marker of apoptosis). These effects were noticed at a low concentration and short exposure time. In the ultrastructural analyses, the treated parasites showed mitochondrial disruption, presence of electron-dense structures and chromatin condensation. These results suggest that this natural compound induces oxidative stress and mitochondrial-dependent apoptosis on Leishmania without disturbing the plasma membrane.

Activity of (-)alpha-bisabolol against Leishmania infantum promastigotes.

Many of the drugs used to treat leishmaniasis are associated with numerous adverse effects. Agents of natural origin have shown activity against different parasites. With this background, an in vitro study was conducted on the activity of (-)alpha-bisabolol, the principal component of Chamomilla recutita essential oil, against Leishmania infantum promastigotes, the main species responsible for human leishmaniasis in Spain. At the two highest concentrations tested (1000 and 500mug/ml), (-)alpha-bisabolol and pentamidine (control agent) achieved 100% inhibition of L. infantum promastigote. These in vitro data can be considered promising in support of the therapeutic use of (-)alpha-bisabolol preparations to treat leishmaniasis caused by L. infantum species.