Oral therapy with sertraline, a selective serotonin reuptake inhibitor, shows activity against Leishmania donovani

Objectives: This study was executed to investigate the efficacy of oral therapy and preliminary leishmanicidal mechanism of sertraline, a selective serotonin reuptake inhibitor widely used for the management of depression, against Leishmania donovani, a causative agent of visceral leishmaniasis (VL). Methods: The effect of the drug was determined for: (i) direct promastigote killing by inhibition of MTT reduction and (ii) killing activity against intracellular amastigotes in mouse peritoneal macrophages by microscopic evaluation of surviving amastigotes in macrophages in Giemsa-stained slides. Furthermore, the oral therapy of sertraline against established VL in BALB/c mice was evaluated through estimation of splenic and liver parasite burdens by Leishman Donovan units. Moreover, the preliminary mechanism of action of the drug against promastigotes was assessed by measuring the intracellular ATP levels and oxygen consumption of treated cells. Results: Sertraline killed L. donovani promastigotes and intracellular amastigotes with 50% inhibitory concentrations (IC50) of 2.2 and 2.3 mg/L, respectively. The drug was also effective in eliminating splenic (72%) and liver (70%) parasite loads in infected BALB/c mice through oral therapy. A sertraline-induced fall in cytoplasmic ATP levels and oxygen consumption rate in promastigotes suggests the involvement of an apoptosis mode of cell death in the treated parasites. Conclusions: Sertraline could be a promising pharmacological tool for the oral treatment of VL.