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Hemostasis-inflammation interaction during envenomation by Bothrops jararaca snakes: pathogenesis of thrombocytopenia, and therapeutic anti-ophidian mechanisms of quercetin-3-rutinoside (rutin)

Grant number: 19/07618-6
Support type:Regular Research Grants
Duration: July 01, 2020 - June 30, 2022
Field of knowledge:Biological Sciences - Pharmacology - Toxicology
Principal Investigator:Marcelo Larami Santoro
Grantee:Marcelo Larami Santoro
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Aparecida Sadae Tanaka ; Francisco Rafael Martins Laurindo ; Maria Elisa Peichoto ; Vânia Gomes de Moura Mattaraia

Abstract

Bothrops jararaca snake venom (BjV) remarkably alters Hemostasis and Inflammation, but few studies have examined the interaction between these processes during envenomation, whose understanding is essential to improve the treatment of patients. Various toxins from BjV showing either pro- or anti-hemostatic activities induce bleeding in bitten patients, associated with the presence of thrombocytopenia and coagulopathy. However, it is not known which one induces thrombocytopenia in vivo. Linked to hemostatic changes, proinflammatory toxins promote cell stimulation, and the release of cytokines and reactive species. Since Bothrops envenomation has a complex pathophysiology, and an effective treatment is lacking to prevent secondary complications not treated by specific antivenom therapy - e.g. local inflammatory changes, renal lesions, microangiopathic anemia and hemorrhagic strokes -, it is essential that new ancillary therapeutic compounds be sought to restrain the development of such manifestations induced by BjV. In previous studies from our group, rutin (quercetin-3-rutinoside) - a cheap and commercially available flavonoid that has well-established antioxidant, anti-inflammatory and pro-hemostatic activities - has proven to be efficacious in combating the hemostatic disorders occurring during envenomation. Thus, this proposal aims to: (1) isolate and characterize BjV toxins that induce thrombocytopenia during envenomation, and to investigate their mechanisms of action, particularly in microcirculation; (2) to investigate in conventional and genetically-modified animal models (a) the pathogenesis of BjV-induced changes in the inflammation-coagulation interface, and (b) the therapeutic activity and mechanism of action of rutin. (AU)