Abstract
Bufotenine is an alkaloid derived from serotonin, structurally similar to LSD and psilocin. This molecule is able to inhibit the rabies virus infection in in vitro and in vivo models, increasing the survival rate of infected animals. Being a very promising molecule for an incurable disease and because of the fact that there is no consensus regarding its neurological effects, this study aimed to evaluate chronic treatment of bufotenine on behavior, pathophysiology, and pharmacokinetics of mice. Animals were daily treated for 21 consecutive days with 0.63, 1.05, and 2.1 mg/animal/day bufotenine and evaluated by open field test and physiological parameters during all the experiment. After this period, organs were collected for histopathological and biodistribution analysis. Animals treated with bufotenine had mild behavioral alterations compared to the control group, being dose-response relationship. On the other hand, animals showed normal physiological functions and no histological alterations in the organs. With high doses, an inflammatory reaction was observed in the site of injection, but with no cellular damage. The alkaloid could be found in the heart and kidney with all doses and in the lungs and brain with higher doses. These results show that the effective dose, 0.63 mg/day, is safe to be administered in mice, since it did not cause significant effects on the animals' physiology and on the CNS. Higher doses were well tolerated, causing only mild behavioral effects. Thus, bufotenine might be a drug prototype for rabies treatment, an incurable disease.
Highlights
Bufotenine, a tryptamine alkaloid resulting from the methylation of serotonin, is a common metabolite spread throughout different living organisms, that can be found, for instance, in the skin secretion of many Brazilian toads of Rhinella genus [1] as well as in plants of Leguminosae family [2, 3]
All in vivo experiments were approved by the Ethic Committee on Animal Use of the Butantan Institute (CEUAIB), under protocol number CEUA 9532050216, which was in accordance with the rules issued by the National Council for Control of Animal Experimentation (CONCEA)
Animals treated with bufotenine displayed different symptoms, which varied in intensity, during the first 50 minutes after the inoculation (Figure 1)
Summary
Bufotenine, a tryptamine alkaloid resulting from the methylation of serotonin, is a common metabolite spread throughout different living organisms, that can be found, for instance, in the skin secretion of many Brazilian toads of Rhinella genus [1] as well as in plants of Leguminosae family [2, 3]. When performing biological-driven studies, our group found that bufotenine can inhibit rabies virus infection on mammalian cultured cells, in a dose- and time-dependent manner [12]. It presents a synergic antiviral effect with a synthetic tetrapeptide derived from the natural antimicrobial peptide ocellatin-F1, which sequence is similar to that of the rabies virus glycoprotein region supposed to mediate the virus internalization [13, 14]. Bufotenine showed to act through an apparent competitive mechanism of action with the rabies virus for the cellular receptors/molecules responsible for its internalization. Thorough characterization of this bioactive effect requires complementary studies in order to be fully elucidated
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