Bufotenine and new perspectives for the treatment of rabies

By Hugo Vigerelli, Postdoctoral researcher Laboratory of Genetics, and Daniel Carvalho Pimenta, Scientific researcher VI, Laboratory of Biochemistry and Biophysics, Butantan Institute, São Paulo, SP, Brazil

The article “Bufotenine, a tryptophan-derived alkaloid, suppresses the symptoms and increases the survival rate of rabies-infected mice: the development of a pharmacological approach for rabies treatment”, published in the Journal of Venomous Animals and Toxins including Tropical Diseases (vol. 26), presents the biological effect of bufotenine – a rather common alkaloid found in many organisms – over rabies, an ancient yet uncurable disease. The study was carried out by researchers at the Butantan Institute, in collaboration with the Brazilian Pasteur Institute, a world reference in the diagnosis of rabies. This project, conducted between 2016 and 2018, was a consequence of a previous observation by the same group that bufotenine was able to inhibit rabies virus infection in cell culture models. The next step was to test this hypothesis in animal models. Therefore, the study revealed that not only bufotenine delays the onset of rabies symptoms, but it also significantly increases the survival rate of infected animals. It is noteworthy to mention that we are not proposing bufotenine as the medicine or drug for the treatment of this disease. However, we highlight the potential that this alkaloid presents to study the biological and molecular mechanisms of the etiology of rabies and possibility of it becoming a scaffold for the development of new synthetic molecules that would eventually become medicines against rabies.

The project was carried out by Hugo Vigerelli who, during his masters and doctorate projects, investigated the effects of bufotenine in rabies infection models, supervised by Daniel Carvalho Pimenta, a scientific researcher at the Laboratory of Biochemistry and Biophysics in Butantan Institute. Hugo and Daniel stablished a partnership between the Butantan Institute (their headquarters, where they conducted all the biochemical steps required for the isolation and characterization of both amphibian and plant seed bufotenine), with the Brazilian Pasteur Institute, a reference in rabies virus research and diagnosis.

Image adapted from the original by Smart – Servier Medical Art by Servier.

Figure 1. Subcutaneous inoculation of bufotenine is able to increase the survival rate of intracerebrally virus-infected mice from 15 to 40%

Rabies is a disease that is present in more than 150 countries and territories, causing the death of 40,000 to 70,000 people every year. Although it is an antique disease, it remains uncurable. Our results show that bufotenine is capable of inhibiting different variants of the virus (in cell cultures), being effective over both laboratory and street viruses, an important result since laboratory viruses may lose some virulence factors. Animal experiments have shown that bufotenine is able to delay the onset of symptoms, a very significant finding, since current rabies treatment protocols consist of keeping the patients alive as long as possible, so that their immune system becomes able to fight the virus.

Currently, our group aims to understand the mechanism of action of bufotenine. In order to achieve this goal, we have already conducted studies on its biodistribution and behavioral effects so that we could determine a good dose and evaluate possible side effects. We are also investigating the immunological effect of bufotenine on the central nervous system, as well as its direct effects on neuron cells. In addition, we are exploring the effect of different synthetic molecules similar to bufotenine, in the search for new molecules that could, in the future, become a medicine for rabies.

References

CUNHA NETO, R.S., et al. Synergic effects between ocellatin-F1 and bufotenine on the inhibition of BHK-21 cellular infection by the rabies virus. J. Venom. Anim. Toxins incl. Trop. Dis [online]. 2015, vol. 21, 50, ISSN: 1678-9199 [viewed 2 September 2020]. DOI: 10.1186/s40409-015-0048-1. Available from: http://ref.scielo.org/wcc6jn

VIGERELLI, H., et al. Bufotenine is able to block rabies virus infection in BHK-21 cells. J. Venom. Anim. Toxins incl. Trop. Dis [online]. 2014, vol. 20, 45, ISSN: 1678-9199 [viewed 2 September 2020]. DOI: 10.1186/1678-9199-20-45. Available from: http://ref.scielo.org/67fqfs

VIGERELLI, H., et al. Biological effects and biodistribution of bufotenine on mice. Biomed Res Int. [online]. 2018, 1032638, ISSN: 2314-6141 [viewed 2 September 2020]. DOI: 10.1155/2018/1032638. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000854/

Rabies [online]. World Health Organization. 2020 [viewed 2 September 2020]. Available from: https://www.who.int/health-topics/rabies#tab=tab_1

To read the article, access it

VIGERELLI, H., et al. Bufotenine, a tryptophan-derived alkaloid, suppresses the symptoms and increases the survival rate of rabies-infected mice: the development of a pharmacological approach for rabies treatment. J. Venom. Anim. Toxins incl. Trop. Dis [online]. 2020, vol. 26, e20190050, ISSN: 1678-9199 [viewed 2 September 2020]. DOI: 10.1590/1678-9199-jvatitd-2019-0050. Available from: http://ref.scielo.org/2by285

Currículo Lattes – Daniel Carvalho Pimenta <http://lattes.cnpq.br/2791913950833163>

Currículo Lattes – Hugo Vigerelli de Barros <http://lattes.cnpq.br/0831598428009566>

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Instituto Butantan <http://www.butantan.gov.br/>

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Pós-Graduação em Toxinologia – Instituto Butantan <http://posgraduacao.butantan.gov.br/>

Research Gate – Daniel Pimenta <https://www.researchgate.net/profile/Daniel_Pimenta>

Research Gate – Hugo Vigerelli <https://www.researchgate.net/profile/Hugo_Vigerelli>

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Research Gate Project – Rabies <https://www.researchgate.net/project/Rabies-16>

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