Dados do Trabalho

Título

Efficiency evaluation of inflammation neutralization induced by Bothrops atrox venom by metalloprotease inhibitors/chelating agents: preclinical assays in vitro and ex vivo models.

Objetivo (s)

This project aims to evaluate the efficiency of neutralizing the pro-inflammatory activity of B. atrox venom using metalloproteinase inhibitors (batimastat, marimastat) and chelating agents (dimercaprol) in vitro leukocyte culture and whole blood samples collected from Bothrops snakebite patients treated at the Fundação de Medicina Tropical Doutor Heitor Vieira Dourado in Manaus-AM, before antivenom therapy.

Material e Métodos

This research initially focuses on evaluating the inhibition of the caseinolytic activity of B. atrox venom. Various concentrations of batimastat, marimastat (0.1 - 100 μM), and dimercaprol (5 - 2000 μM) were individually incubated with B. atrox venom and in combination with antibothropic serum. With this first test, the ideal concentrations of the inhibitors, the proportions of the antivenom-inhibitor mixtures and the conditions will be established to evaluate, in the future, the neutralizing potential of the inhibitor/chelating agents on the inflammation inhibition assays in vitro and ex vivo.

Resultados e Conclusão

Inhibitory concentration (IC50) of inhibitors for B. atrox venom metalloproteinase activity on casein was 59.02 μM for batimastat, 32.97 μM for marimastat, and 604.5 μM for dimercaprol. The antibothropic serum alone had a 53.11% inhibition of the caseinolytic activity of the B. atrox venom, whereas the combinations of the antibothropic serum with the inhibitors presented an additive pharmacological inhibitory effect.

This is the first study to test matrix metalloproteinase inhibitors and chelating agents in Bothrops atrox venom and our observations in this early stage of the investigation indicate that the drugs used can inhibit the metalloproteinase activity of the venom and point towards their reuse in therapy. Therefore, more in-depth studies are still needed to determine to what extent these drugs can inhibit the inflammation produced by the venom and the mechanisms of action to neutralize it. With this, clinical trials would be justified in order to use them as a complement to antivenin therapy in patients bitten by snakes.

Palavras-chave

Antivenins, matrix metalloproteinase inhibitors, drug repositioning, snakebites.

Agradecimentos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM)