Abstract
BackgroundRabies is a fatal zoonotic neglected disease that occurs in more than 150 countries, and kills more than 55.000 people every year. It is caused by an enveloped single stranded RNA virus that affects the central nervous system, through an infection initiated by the muscular nicotinic acetylcholine receptor, according to many authors. Alkaloids, such as acetylcholine, are widespread molecules in nature. They are present in numerous biological fluids, including the skin secretion of many amphibians, in which they act (together with proteins, peptides and steroids) as protection agents against predators and/or microorganisms. Among those amphibians that are rich in alkaloids, there is the genus Rhinella.MethodsBufotenine was isolated from Rhinela jimi skin secretion after a liquid-liquid partition (H2O:CH2Cl2) and reversed phase high-performance liquid chromatography analyses (RP-HPLC). Bufotenine was also extracted from seeds of Anadenanthera colubrina in acetone solution and purified by RP-HPLC, as well. Structural characterization was performed by mass spectrometry and nuclear magnetic resonance analyses. Cytotoxic tests of bufotenine were performed over baby hamster kidney (BHK-21) cells using MTT test. For the antiviral activity, Rabies virus strain Pasteur vaccine (PV) was used on fluorescence inhibition test and fluorescent foci inhibition test, with both simultaneous and time course treatment of the cells with the virus and bufotenine.ResultsIn the present work we describe the effects of bufotenine, obtained either from toads or plants, that can inhibit the penetration of rabies virus in mammalian cells through an apparent competitive mechanism by the nicotinic acetylcholine receptor. Moreover, this inhibition was dose- and time-dependent, pointing out to a specific mechanism of action.ConclusionsThis work do not present or propose bufotenine as a drug for the treatment of rabies due to the hallucinogen and psychotropic effects of the molecule. However, continued studies in the elucidation of the antiviral mechanism of this molecule, may lead to the choice or development of a tryptamine analogue presenting potential clinical use.Electronic supplementary materialThe online version of this article (doi:10.1186/1678-9199-20-45) contains supplementary material, which is available to authorized users.
Highlights
Rabies is a fatal zoonotic neglected disease that occurs in more than 150 countries, and kills more than 55.000 people every year
Taking into account that the rabies virus can bind to the nicotinic acetylcholine receptor, and that other alkaloids can bind to these receptors, the aim of this study was to evaluate the effects of bufotenine as a possible interfering agent in the process of infection of the rabies virus in mammalian cells, using the simplified fluorescent inhibition microtest (SFIMT) and rapid fluorescent focus inhibition test (RFFIT) techniques
reversed phase high-performance liquid chromatography analyses (RP-HPLC) and mass spectrometry analysis RP-HPLC analysis of the aqueous partition of Rhinela jimi skin secretion showed the presence of five major HPLC peaks (Figure 1A)
Summary
Rabies is a fatal zoonotic neglected disease that occurs in more than 150 countries, and kills more than 55.000 people every year It is caused by an enveloped single stranded RNA virus that affects the central nervous system, through an infection initiated by the muscular nicotinic acetylcholine receptor, according to many authors. Proteins, peptides, steroids and amines that act as chemical protection agents against predators and/or microorganisms, such as fungi and bacteria [8,11] Among those amphibians that are rich in alkaloids, there is the genus Bufo that was recently split into Bufo in the Old World and Rhinella in the New World [12]. Their secretion contain a large number of alkaloids including bufotenine – a tryptamine alkaloid used as a defense mechanism due to its toxicity – that is found in the Leguminosae family [13,14,15,16]
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