In vivo treatment with varespladib, a phospholipase A2 inhibitor, prevents the peripheral neurotoxicity and systemic disorders induced by Micrurus corallinus (coral snake) venom in rats

Silva-Carvalho, Rosimeire; Gaspar, Matheus Z.; Quadros, Luiz H.B.; Lobo, Luís G.G.; Rogério, Letícia M.; Santos, Najla T.S.; Zerbinatti, Maria C.; Laposy, Cecília Braga; Silva, Elisangela O.; Gerez, Juliana Rubira; Silva, Nelson J.; Lomonte, Bruno; Rowan, Edward G.; Floriano, Rafael Stuani

doi:10.1016/j.toxlet.2021.11.003

Cited by 17 publications

(10 citation statements)

References 51 publications

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“…In our study, we found that pre-incubation with Varespladib prevented both the neurotoxic and myotoxic effects of D. siamensis venom, indicating the key role PLA 2 toxins play in these effects. Our findings support previous reports showing that Varespladib prevents PLA 2 -mediated neurotoxicity and myotoxicity across a diverse range of snake venoms [ 23 , 24 , 25 , 45 , 47 , 48 , 57 , 58 , 59 , 60 ]. The important role of PLA 2 toxins in Daboia spp .…”

Section: Discussionsupporting

confidence: 92%

“…These observations support in vivo experiments in mice, where Varespladib was able to inhibit the myotoxic effects of four Chinese snake venoms [ 44 ] as well as attenuate the myonecrotic and haemorrhagic activity induced by Deinagkistrodon acutus (sharp-nosed pit viper) venom [ 46 ]. In contrast, the concomitant administration of antivenom and Varespladib appeared to provide additional survival benefits following O. scutellatus [ 49 ], as well as Micrurus corallinus (Coral snake) envenoming [ 60 ] in mice and rats, respectively.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell’s Viper (Daboia siamensis) Venom Toxicity

Lay

Liang²,

Hodgson³

2023

Toxins

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The venom of the Russell’s viper (Daboia siamensis) contains neurotoxic and myotoxic phospholipase A2 toxins which can cause irreversible damage to motor nerve terminals. Due to the time delay between envenoming and antivenom administration, antivenoms may have limited efficacy against some of these venom components. Hence, there is a need for adjunct treatments to circumvent these limitations. In this study, we examined the efficacy of Chinese D. siamensis antivenom alone, and in combination with a PLA2 inhibitor, Varespladib, in reversing the in vitro neuromuscular blockade in the chick biventer cervicis nerve-muscle preparation. Pre-synaptic neurotoxicity and myotoxicity were not reversed by the addition of Chinese D. siamensis antivenom 30 or 60 min after venom (10 µg/mL). The prior addition of Varespladib prevented the neurotoxic and myotoxic activity of venom (10 µg/mL) and was also able to prevent further reductions in neuromuscular block and muscle twitches when added 60 min after venom. The addition of the combination of Varespladib and antivenom 60 min after venom failed to produce further improvements than Varespladib alone. This demonstrates that the window of time in which antivenom remains effective is relatively short compared to Varespladib and small-molecule inhibitors may be effective in abrogating some activities of Chinese D. siamensis venom.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell’s Viper (Daboia siamensis) Venom Toxicity

Lay

Liang²,

Hodgson³

2023

Toxins

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“…In recent years, the PLA 2 antagonistic activity of varespladib ( Lewin et al, 2016 ; Salvador et al, 2019 ; Salvador et al, 2021 ), a synthetic drug developed to treat disturbances of inflammatory cascades associated with high levels of secreted PLA 2 ( Varespladib, 2011 ), has been experimentally explored as an useful therapeutic alternative to complement antivenom therapies applied in envenomations by Elapidae and Viperidae snakes, with potential even to replace them in special situations in which these antivenoms are not available. Varespladib has high efficacy to suppress the systemic effects caused by several venoms from Elapidae ( Lewin et al, 2016 ; Bittenbinder et al, 2018 ; Lewin et al, 2018 ; Wang et al, 2018 ; Oliveira et al, 2020 ; Gutiérrez et al, 2020a ; Dashevsky et al, 2021 ; Kazandjian et al, 2021 ; Silva-Carvalho et al, 2021 ) and Viperidae ( Lewin et al, 2016 ; Wang et al, 2018 ; Youngman et al, 2020 ; Zinenko et al, 2020 ; Gutiérrez et al, 2020a ; Liu et al, 2021 ) snakes. However, there is no report associating the efficacy of varespladib with toxicological aspects of Lachesis venoms.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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Varespladib (VPL) was primarily developed to treat inflammatory disturbances associated with high levels of serum phospholipase A2 (PLA2). VPL has also demonstrated to be a potential antivenom support agent to prevent PLA2-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 PLA2, 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 PLA2in vitro, with VPL abolishing the PLA2 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 PLA2 antagonize activity efficaciously preventing the venom-induced coagulation disturbances.

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“…While the antivenom displayed slight efficacy in isolation against P. volcanicum , its use in combination with small-molecule inhibitors may improve the therapeutic potential. Indeed, several recent studies have shown the therapeutic synergy between small-molecule inhibitors and antivenom for a range of snake venoms [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Antivenom and Small-Molecule Inhibition of Novel Coagulotoxic Variations in Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium American Viperid Snake Venoms

Jones

Youngman

Neri-Castro

et al. 2022

Toxins

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Within Neotropical pit-vipers, the Mexican/Central-American clade consisting of Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium is a wide-ranging, morphologically and ecologically diverse group of snakes. Despite their prevalence, little is known of the functional aspects of their venoms. This study aimed to fill the knowledge gap regarding coagulotoxic effects and to examine the potential of different therapeutic approaches. As a general trait, the venoms were shown to be anticoagulant but were underpinned by diverse biochemical actions. Pseudo-procoagulant activity (i.e., thrombin-like), characterized by the direct cleavage of fibrinogen to form weak fibrin clots, was evident for Atropoides picadoi, Cerrophidiontzotzilorum, Metlapilcoatlus mexicanus, M. nummifer, M. occiduus, M. olmec, and Porthidium porrasi. In contrast, other venoms cleaved fibrinogen in a destructive (non-clotting) manner, with C. godmani and C. wilsoni being the most potent. In addition to actions on fibrinogen, clotting enzymes were also inhibited. FXa was only weakly inhibited by most species, but Cerrophidion godmani and C. wilsoni were extremely strong in their inhibitory action. Other clotting enzymes were more widely inhibited by diverse species spanning the full taxonomical range, but in each case, there were species that had these traits notably amplified relatively to the others. C. godmani and C. wilsoni were the most potent amongst those that inhibited the formation of the prothrombinase complex and were also amongst the most potent inhibitors of Factor XIa. While most species displayed only low levels of thrombin inhibition, Porthidium dunni potently inhibited this clotting factor. The regional polyvalent antivenom produced by Instituto Picado Clodomiro was tested and was shown to be effective against the diverse anticoagulant pathophysiological effects. In contrast to the anticoagulant activities of the other species, Porthidium volcanicum was uniquely procoagulant through the activation of Factor VII and Factor XII. This viperid species is the first snake outside of the Oxyuranus/Pseudonaja elapid snake clade to be shown to activate FVII and the first snake venom of any kind to activate FXII. Interestingly, while small-molecule metalloprotease inhibitors prinomastat and marimastat demonstrated the ability to prevent the procoagulant toxicity of P. volcanicum, neither ICP antivenom nor inhibitor DMPS showed this effect. The extreme variation among the snakes here studied underscores how venom is a dynamic trait and how this can shape clinical outcomes and influence evolving treatment strategies.

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In vivo treatment with varespladib, a phospholipase A2 inhibitor, prevents the peripheral neurotoxicity and systemic disorders induced by Micrurus corallinus (coral snake) venom in rats

Cited by 17 publications

References 51 publications

In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell’s Viper (Daboia siamensis) Venom Toxicity

In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell’s Viper (Daboia siamensis) Venom Toxicity

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

Differential Antivenom and Small-Molecule Inhibition of Novel Coagulotoxic Variations in Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium American Viperid Snake Venoms

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