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| Author(s): |
Ana Teresa Azevedo Sachetto
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2022-03-25 |
| Examining board members: |
Marcelo Larami Santoro;
André Rolim Baby;
Sergio Paulo Bydlowski;
Andre Lopes Fuly
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| Advisor: | Marcelo Larami Santoro |
| Abstract | |
Bothrops jararaca snake venom (BjV) induces several deleterious alteration to the organism, as thrombocytopenia, hypofibrinogenemia, intense local hemorrhage, oxidative/nitrosative stress and an exacerbated inflammatory response. Patient tratement still presents challenges since antivenom therapy presents limitation regarding its actions. On a previous study, rutin potential was demonstrated as a possible complementary agent to snakebites. Rutin possessed a range of activities, however its use presents limitations due to its low hydrosolubility. Therefore, this project was initiated by modifying rutin chemically by succinylation, resulting in the water-soluble compound rutin succinate. Rutin succinate demonstrated similar characteristic activities as rutin in vitro, as an antioxidant and inhibitor of protein disulfide isomerase (PDI). Tests in vitro were performed to compared rutin and rutin succinate to evaluate possible inhibitory activities against BjV. Differently from rutin, rutin succinate showed inhibitory potential regarding the major protein family in BjV (metalloproteinases). In vivo experimental envenomation tests were carried out using 2 and 3 LD50 (lethal dose 50%) of BjV, which showed that rutins induce an improved recovery of hemostatic parameters altered by envenomation. Furthermore, rutin and rutin succinate were able to neutralize BjV toxic effects and prevent venom-induced mortality of mice. Posteriorly, in vivo tests were perfomed with a sublethal dose of BjV to assess coagulation and inflammation parameters and local hemorrhage. Rutin succinate pre-incubated with BjV inhibited important metalloproteinases activities, completely abolished local hemorrhage and decreased levels of the pro-inflammatory cytokine IL-6. Results also demonstrated that tissue factor (TF) has a protective hemostatic role in envenomation. Differently, endotoxemia an experimental model with better elucidated mechanism induces pro-coagulant and proinflammatory states dependent of TF. In despite of differences between the two models, an increase in genes that code acute phase proteins was observed in envenomation and endotoxemia. As on envenomation, rutins presented an anti-inflammatory activity on endotoxemia, however in a more limited manner. Therefore, rutin and rutin succinate demonstrated different mechanisms of action regarding venom and beneficial effects when administrated as treatments in both envenomation and endotoxemia. In addition, the administration of rutin and rutin succinate associated or not to antivenom improved the recovery of thrombocytopenia and fibrinogen levels and diminished local hemorrhage, showing great potential as treatments for snakebites (AU) | |
| FAPESP's process: | 18/26015-8 - Novel mechanisms of pathogenesis of Sepsis and Bothrops envenomation: potential of rutin as a therapeutic agent |
| Grantee: | Ana Teresa Azevedo Sachetto |
| Support Opportunities: | Scholarships in Brazil - Doctorate |