Varespladib (LY315920) prevents neuromuscular blockage and myotoxicity induced by crotoxin on mouse neuromuscular preparations

Maciel, Fernanda Valadares; Pinto, Êmylle Karoline Ramos; Souza, Natália Muradas Valério; Abreu, Thales Augusto Gonçalves de; Ortolani, Paula Ladeira; Fortes-Dias, Consuelo Latorre; Cavalcante, Walter Luís Garrido

doi:10.1016/j.toxicon.2021.09.009

Cited by 13 publications

(7 citation statements)

References 41 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%

“…However, the administration of a combination of antivenom and Varespladib after venom addition did not result in an additive or synergistic inhibitory effect against the neurotoxic or myotoxic effects. A similar finding of greater efficacy of Varespladib over antivenom has also been reported against O. scutellatus venom, an elapid venom with PLA 2 -mediated neurotoxicity [ 23 ], and C. d. terrificus venom, from a viperid with PLA 2 -mediated neurotoxicity and myotoxicity [ 24 , 25 ]. 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 ].…”

Section: Discussionsupporting

confidence: 67%

“…Those present in elapids are categorised within group I, whereas those found in Viperidae venoms are within group II [ 21 , 22 ]. Such toxins have been reported to be responsible for neurotoxicity (i.e., taipoxin from Oxyuranus scutellatus, Coastal taipan) [ 16 , 23 ], myotoxicity (i.e., crotoxin from Crotalus durissus terrificus, South American rattlesnake) [ 24 , 25 ], pain and oedema, cardiovascular disturbances, haemolysis and coagulation disorders, amongst other effects [ 18 , 26 , 27 , 28 , 29 , 30 ].…”

Section: Introductionmentioning

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: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

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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“…Therefore, our results are not comparable to Gutierrez et al [ 38 ]. The inhibitory activity of varespladib on the C. durissus sub-species venoms, including C. d. cumanensis may be explained by the ability of this compound to inhibit the crotoxin complex, its PLA 2 , in their capacity to induce neuromuscular blockade and myotoxicity [ 39 ], which agrees with the inhibition of myotoxicity and edema-forming activity induced by C. d. cumanensis reported in our study.…”

Section: Discussionsupporting

confidence: 87%

Inhibitory Effects of Varespladib, CP471474, and Their Potential Synergistic Activity on Bothrops asper and Crotalus durissus cumanensis Venoms

et al. 2022

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Snakebite is a neglected tropical disease that causes extensive mortality and morbidity in rural communities. Antivenim sera are the currently approved therapy for snake bites; however, they have some therapeutic limitations that have been extensively documented. Recently, small molecule toxin inhibitors have received significant attention as potential alternatives or co-adjuvant to immunoglobulin-based snakebite therapies. Thus, in this study, we evaluated the inhibitory effects of the phospholipase A2 inhibitor varespladib and the metalloproteinase inhibitor CP471474 and their synergistic effects on the lethal, edema-forming, hemorrhagic, and myotoxic activities of Bothrops asper and Crotalus durissus cumanensis venoms from Colombia. Except for the preincubation assay of the lethal activity with B. asper venom, the mixture showed the best inhibitory activity. Nevertheless, the mix did not display statistically significant differences to varespladib and CP471474 used separately in all assays. In preincubation assays, varespladib showed the best inhibitory activity against the lethal effect induced by B. asper venom. However, in independent injection assays, the mix of the compounds partially inhibited the lethal activity of both venoms (50%). In addition, in the assays to test the inhibition of edema-forming activity, the mixture exhibited the best inhibitory activity, followed by Varespladib, but without statistically significant differences (p > 0.05). The combination also decreased the myotoxic activity of evaluated venoms. In these assays, the mix showed statistical differences regarding CP471474 (p < 0.05). The mixture also abolished the hemorrhagic activity of B. asper venom in preincubation assays, with no statistical differences to CP471474. Finally, the mixture showed inhibition in studies with independent administration in a time-dependent manner. To propose a mode of action of varespladib and CP471474, molecular docking was performed. PLA2s and SVMPs from tested venoms were used as targets. In all cases, our molecular modeling results suggested that inhibitors may occupy the substrate-binding cleft of the enzymes, which was supported by specific interaction with amino acids from the active site, such as His48 for PLA2s and Glu143 for the metalloproteinase. In addition, varespladib and CP471474 also showed interaction with residues from the hydrophobic channel in PLA2s and substrate binding subsites in the SVMP. Our results suggest a synergistic action of the mixed inhibitors and show the potential of varespladib, CP471474, and their mixture to generate new treatments for snakebite envenoming with application in the field or as antivenom co-adjuvants.

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“…In recent years, several neuro and myotoxins have been isolated from snake venoms, and the mechanism of action of their components has been investigated [2,3,8,29], since crotamine is one of the important components of Crotalidae venom that combines cytotoxic and neurotoxic properties [5], it was carried out this study of the alterations in the neuro-motor plates produced by the action of purified C-L as described in results sections.…”

Section: Resultsmentioning

confidence: 99%

A new crotamine-like from the rattlesnake (Crotalus durissus cumanensis) venom causing damages: Qualitative and Quantitative Cytotoxic Studies on subcellular and neuromuscular structures

et al. 2022

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A quantitative model to expose the adrenal gland sub-cellular alterations produced by crotamine-like (C-L) from rattlesnake venom during 3, 6 and 24 hours (h), and also qualitative changes on mice neuromuscular structures in vivo were observed and calculated by transmission electron microscopy. A pure crotamine-like (C-L) isoform was obtained using a cationic exchange chromatography column from the rattlesnake Crotalus durissus cumanensis venom. The C-L SDS-PAGE (15.5 %) under non-reduced conditions exhibited a molecular mass of ~3 kDa single band. The C-L in vivo qualitative experiments induced ultrastructural changes in mouse neuromuscular structures at 3, 6 and 24 h, such as reduction in the number of acetylcholine vesicles, disorganisation of the secondary synaptic clefts, enlargement of the sub-sarcolemma space and alteration of the mitochondria morphology, number and cristae. Regarding neurotoxic actions in vivo, the animals injected with C-L presented spastic paralysis of the hind limbs. The quantitative alterations studied on the capillaries, the nucleus, the mitochondria the lipid inclusions, and the smooth endoplasmic reticulum were observed from 3 to 24 h after C-L injection. As far as it is known from the literature review, there are no quantitative records of similar sub-cellular alterations caused by crotamine.

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Varespladib (LY315920) prevents neuromuscular blockage and myotoxicity induced by crotoxin on mouse neuromuscular preparations

Cited by 13 publications

References 41 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

Inhibitory Effects of Varespladib, CP471474, and Their Potential Synergistic Activity on Bothrops asper and Crotalus durissus cumanensis Venoms

A new crotamine-like from the rattlesnake (Crotalus durissus cumanensis) venom causing damages: Qualitative and Quantitative Cytotoxic Studies on subcellular and neuromuscular structures

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