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Assessment of the protective action of varespladib (LY315920), a phospholipase A2 inhibitor, on the hemorrhagic and proteolytic effects of Lachesis muta rhombeata (Surucucu Sul-Americana) venom

Grant number: 20/11268-8
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2021
Effective date (End): February 28, 2022
Field of knowledge:Biological Sciences - Pharmacology - Toxicology
Principal researcher:Rafael Stuani Floriano
Grantee:Pamella Godinho Gutierres
Home Institution: Pró-Reitoria de Pesquisa e Pós-Graduação. Universidade do Oeste Paulista (UNOESTE). Presidente Prudente , SP, Brazil

Abstract

Envenomation by Lachesis is characterized by clinical manifestations such as local and systemic myonecrosis, renal dysfunction, hemorrhagic, coagulopathic and hypotensive activities. The treatment of envenomation by Lachesis is conditioned to serotherapy and there are few reports related to application of other therapeutics pathways. Recent studies have shown that varespladib (LY315920), a phospholipase A2 (PLA2) inhibitor, can be used as a potential coadjutant agent to serotherapy in envenomation by Viperidae and Elapidae snakes. In this project, we aim to assess the protective action of varespladib, associated or not to polyvalent anti-Bothrops/Lachesis serum, on the hemorrhagic and proteolytic action of the Lachesis muta rhombeata (Sul-American bushmaster) in animal experimentation models in vitro and in vivo. For in vitro protocols, the inhibitory action of varespladib, associated or not to antivenom, on the enzymatic action (PLA2 and proteases) of the L. m. rhombeata venom will be assessed through spectrophotometry, including the action of these agents on the coagulation time for prothrombin, thrombin and activated partial thromboplastin in citrated plasm from rat using kits for coagulometry. For in vivo protocols, the inhibitory action of both agents on the haemorrhagic effect of L. m. rhombeata venom will be assess by inducing subcutaneous hemorrhagic halo in rats. In addition, the local and systemic myotoxicity will be assessed in rats grouped in: (1) control, (2) venom, (3) varespladib, (4) venom + varespladib, (5) venom + antivenom and (6) venom + varespladib + antivenom; the animals will be monitored (rectal temperature, ambulation, occurrence of haemorrhage and oedema formation) at T0, T30, T60, T90 and T120 min, followed by euthanasia and blood samples collection for plasmatic creatine kinase (CK) release analysis, including contralateral gastrocnemius muscle samples for histopathological analysis. The results of this study will contribute to understand the therapeutic action of varespladib on the effects induced by envenomation by Lachesis.