AUTHOR=Gutierres Pamella G. , Pereira Diego R. , Vieira Nataly L. , Arantes Lilian F. , Silva Nelson J. , Torres-Bonilla Kristian A. , Hyslop Stephen , Morais-Zani Karen , Nogueira Rosa M. B. , Rowan Edward G. , Floriano Rafael S. 

TITLE=Action of Varespladib (LY-315920), a Phospholipase A2 Inhibitor, on the Enzymatic, Coagulant and Haemorrhagic Activities of Lachesis muta rhombeata (South-American Bushmaster) Venom

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.812295

DOI=10.3389/fphar.2021.812295

ISSN=1663-9812

ABSTRACT=<p>Varespladib (VPL) was primarily developed to treat inflammatory disturbances associated with high levels of serum phospholipase A<sub>2</sub> (PLA<sub>2</sub>). VPL has also demonstrated to be a potential antivenom support agent to prevent PLA<sub>2</sub>-dependent effects produced by snake venoms. In this study, we examined the action of VPL on the coagulant, haemorrhagic and enzymatic activities of <italic>Lachesis muta rhombeata</italic> (South-American bushmaster) venom. Conventional colorimetric enzymatic assays were performed for PLA<sub>2</sub>, caseinolytic and esterasic activities; <italic>in vitro</italic> 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<sub>2</sub><italic>in vitro</italic>, with VPL abolishing the PLA<sub>2</sub> 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 <italic>in vitro</italic>, 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 <italic>L. m. rhombeata</italic> venom, with its high PLA<sub>2</sub> antagonize activity efficaciously preventing the venom-induced coagulation disturbances.</p>