ction of Varespladib (LY-315920), a Phospholipase A(2) Inhibitor, on the Enzymatic, Coagulant and Haemorrhagic Activities of Lachesis muta rhombeata (South-American Bushmaster) Veno

Author(s):Show less -

Gutierres, Pamella G. ^[1] ; Pereira, Diego R. ^[1] ; Vieira, Nataly L. ^[1] ; Arantes, Lilian F. ^[2] ; Silva, Jr., Nelson J. ^[3] ; Torres-Bonilla, Kristian A. ^[4] ; Hyslop, Stephen ^[4] ; Morais-Zani, Karen ^[5] ; Nogueira, Rosa M. B. ^[1] ; Rowan, Edward G. ^[6] ; Floriano, Rafael S. ^[1]

Affiliation

^[1] Univ Western Sao Paulo, Lab Toxinol & Cardiovasc Res, Presidente Prudente - Brazil

^[2] Rural Fed Univ Pernambuco, Grad Program Zootech, Recife, PE - Brazil

^[3] Pontifical Catholic Univ Goias, Sch Med Pharmaceut & Biomed Sci, Grad Program Environm Sci & Hlth, Goiania, Go - Brazil

^[4] Univ Estadual Campinas, Fac Med Sci, Dept Pharmacol, Campinas - Brazil

^[5] Butantan Inst, Lab Herpetol, Sao Paulo - Brazil

^[6] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow, Lanark - Scotland

• Document type: Journal article
• Source: FRONTIERS IN PHARMACOLOGY; v. 12, JAN 12 2022.
• Web of Science Citations: 0

Abstract

Varespladib (VPL) was primarily developed to treat inflammatory disturbances associated with high levels of serum phospholipase A(2) (PLA(2)). VPL has also demonstrated to be a potential antivenom support agent to prevent PLA(2)-dependent effects produced by snake venoms. In this study, we examined the action of VPL on the coagulant, haemorrhagic and enzymatic activities of Lachesis muta rhombeata (South-American bushmaster) venom. Conventional colorimetric enzymatic assays were performed for PLA(2), caseinolytic and esterasic activities; in vitro coagulant activities for prothrombin time (PT) and activated partial thromboplastin time (aPTT) were performed in rat citrated plasma through a quick timer coagulometer, whereas the dimensions of haemorrhagic haloes obtained after i.d. injections of venom in Wistar rats were determined using ImageJ software. Venom (1 mg/ml) exhibited accentuated enzymatic activities for proteases and PLA(2) in vitro, with VPL abolishing the PLA(2) activity from 0.01 mM; VPL did not affect caseinolytic and esterasic activities at any tested concentrations (0.001-1 mM). In rat citrated plasma in vitro, VPL (1 mM) alone efficiently prevented the venom (1 mg/ml)-induced procoagulant disorder associated to extrinsic (PT) pathway, whereas its association with a commercial antivenom successfully prevented changes in both intrinsic (aPTT) and extrinsic (PT) pathways; commercial antivenom by itself failed to avoid the procoagulant disorders by this venom. Venom (0.5 mg/kg)-induced hemorrhagic activity was slightly reduced by VPL (1 mM) alone or combined with antivenom (antivenom:venom ratio 1:3 `v/w') in rats, with antivenom alone producing no protective action on this parameter. In conclusion, VPL does not inhibit other major enzymatic groups of L. m. rhombeata venom, with its high PLA(2) antagonize activity efficaciously preventing the venom-induced coagulation disturbances. (AU)

• FAPESP's process: 20/11268-8 - 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
• Grantee: Pamella Godinho Gutierres
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/04287-6 - Structural and pharmacological characterization of toxins isolated from Bothrops bilineatus smaragdinus (forest viper) venom with potential modulatory activity of the motor synaptic release and cardiovascular functions
• Grantee: Rafael Stuani Floriano
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants