Combinations of Alkaloids Affecting Different Molecular Targets with the Saponin Digitonin Can Synergistically Enhance Trypanocidal Activity against Trypanosoma brucei brucei

Abstract

The flagellate Trypanosoma brucei causes sleeping sickness in humans and nagana in animals. Only a few drugs are registered to treat trypanosomiasis, but those drugs show severe side effects. Also, because some pathogen strains have become resistant, new strategies are urgently needed to combat this parasitic disease. An underexplored possibility is the application of combinations of several trypanocidal agents, which may potentiate their trypanocidal activity in a synergistic fashion. In this study, the potential synergism of mutual combinations of bioactive alkaloids and alkaloids with a membrane-active steroidal saponin, digitonin, was explored with regard to their effect on T. b. brucei. Alkaloids were selected that affect different molecular targets: berberine and chelerythrine (intercalation of DNA), piperine (induction of apoptosis), vinblastine (inhibition of microtubule assembly), emetine (intercalation of DNA, inhibition of protein biosynthesis), homoharringtonine (inhibition of protein biosynthesis), and digitonin (membrane permeabilization and uptake facilitation of polar compounds). Most combinations resulted in an enhanced trypanocidal effect. The addition of digitonin significantly stimulated the activity of almost all alkaloids against trypanosomes. The strongest effect was measured in a combination of digitonin with vinblastine. The highest dose reduction indexes (DRI) were measured in the two-drug combination of digitonin or piperine with vinblastine, where the dose of vinblastine could be reduced 9.07-fold or 7.05-fold, respectively. The synergistic effects of mutual combinations of alkaloids and of alkaloids with digitonin present a new avenue to treat trypanosomiasis but one which needs to be corroborated in future animal experiments.T rypanosoma brucei is a single-celled protozoan that, if left untreated, can cause the deadly sleeping sickness (human African trypanosomiasis [HAT]). Two trypanosome subspecies affect people: T. b. gambiense (found in western and central Africa) and T. b. rhodesiense (in eastern and southern Africa). The disease caused by T. b. gambiense is more abundant and accounts for more than 98% of all infections of patients. Infected persons go through two stages of the disease. The first or hemolymphatic phase causes fever, itching, and headache. In the second or neurological stage, the blood-brain barrier is crossed by the parasite and the central nervous system is affected. This is the stage at which the disturbance of the sleep cycle appears (hence the name of the disease). The vector of T. brucei is the tsetse fly (genus Glossina), which can transmit the parasite to a diversity of mammalian hosts, including humans (1, 2).Only four drugs are registered for treatment of the disease. Suramin and pentamidine are used for the first stage of the sleeping sicknesses caused by T. b. rhodesiense and T. b. gambiense, respectively. Melarsoprol is registered for treatment of the neurological stage. Eflornithine is a drug which is less toxic than melarsoprol but is effective on...

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