Abstract
Snakebites are a major Collective Health problem worldwide. In Brazil, Bothrops jararaca snake venom (BjV) evokes hemostatic disturbances, bleeding manifestations, and redox status imbalance. Specific antivenom therapy, although efficacious to revert most snakebite-induced manifestations, is incapable of treating secondary manifestations, such as oxidative/nitrosative stress. Searching for new complementary therapies that could attenuate physiological derangements triggered by envenomation, we elected to test quercetin-3-rutinoside (rutin) by its potential as both a potent antioxidant and a hemostasis modulatory compound. The activity of rutin was evaluated both on the biological activities of crude BjV in vitro, and in vivo by the ability of rutin (14.4 mg/kg b.w.) to modulate hematological, hemostatic and redox status markers altered by BjV injection (1.6 mg/kg b.w., s.c.) in mice. In vitro, rutin failed to inhibit BjV-induced platelet aggregation and biological activities of major BjV enzymes (metalloproteinases, phospholipases A2, serine proteases, and L-amino acid oxidases). On the other hand, rutin attenuated local hemorrhage, and the increase in reactive species, prevented the fall in RBC counts and fibrinogen levels, diminished tail bleeding and shortened prothrombin time (PT) evoked by envenomation. Furthermore, rutin reduced tissue factor (TF) activity and altered the protein expression of TF in liver, lungs, heart and skin. In conclusion, the disturbances in redox status and hemostatic system induced by B. jararaca envenomation were modulated by rutin, suggesting it has a great potential to be used as an ancillary therapeutic agent for snakebites.
Highlights
Worldwide, snakebites are considered a major public health issue, and, acknowledging that, the World Health Organization (WHO) declared snakebite envenomation as a neglected tropical disease
Bothrops jararaca venom (BjV) is composed by a complex mixture of proteins, and most of them are grouped into the following families: snake venom metalloproteinases (SVMP), snake venom serine proteinases (SVSP), type-C lectins, phospholipases A2 (PLA2) and L-amino acid oxidases (LAAO) [3]
A potent antioxidant that controls thrombus growth and regulates ROS/RNS generation, we could address the link between generation of reactive species, tissue factor (TF) decryption/encryption and hemostatic disturbances during B. jararaca envenomation; in addition, we investigated whether rutin could be used as a putative ancillary treatment to B. jararaca envenomation
Summary
Snakebites are considered a major public health issue, and, acknowledging that, the World Health Organization (WHO) declared snakebite envenomation as a neglected tropical disease. Bothrops jararaca venom (BjV) is composed by a complex mixture of proteins, and most of them are grouped into the following families: snake venom metalloproteinases (SVMP), snake venom serine proteinases (SVSP), type-C lectins, phospholipases A2 (PLA2) and L-amino acid oxidases (LAAO) [3]. These proteins are responsible for the toxic activity of BjV, and evoke clinical disturbances in snakebite victims, such as intense inflammatory reactions (edema, local bleeding, and necrosis) at the site of the bite, and systemic bleeding (gingival bleeding, ecchymosis, petechiae, hematuria, epistaxis, and hemoptysis) [4]. Several mechanisms have been attributed to modulate TF function, and among them, the controversial regulatory activity of PDI, which is a thiol-isomerase and oxi-reductase chaperone that is required for thrombus formation in vivo and that has been reported to form an allosteric Cys186–Cys209 disulfide bond in TF, which is essential to its coagulating activity [7,8,9]
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